PT94338A - METHOD FOR THE PREPARATION OF DIBENZENE (1,5) DIOXOCIN-5-ONA DERIVATIVES AND THEIR USE FOR MEDICINES - Google Patents

Abstract

The present invention relates to 7H-dibenzo[1,5]-dioxocin-5-ones of the general formula (I) <IMAGE> in which R<1> - R<8>, R<14> and R<15> have the meaning given in the description, to their use in medicaments, and processes for their preparation, in particular their use in medicaments having a circulatory activity.

Description

The present invention relates to 7H-dibenzo [1,2,5] dioxocin-5-ones, and further relates to their use in medicaments, and to processes for the preparation of these compounds, in particular their use in drugs having a circulation effect blood.

Tetrahedron Letters Vol. 45, 3941-3942 (1974) discloses the formula of a natural substance named penicillide, the monomethyl ether of which seems to exert an inhibitory effect on the germination of &quot; Indicate as a preparation process the extraction from the mycelium of a fungus of the species Penicillium, which, however, is not clearly described in terms of its taxonomic classification. Due to the insufficient indications given in that specification, the preparation process is not reproducible and thus the said natural substance is not accessible to the public. The present invention provides, for the first time, reproducible processes for the preparation of these compounds becoming accessible to the public and, at the same time, claims its first therapeutic application. The present invention relates to compounds of general formula (1)

R8 and R5 are the same or different and in the case of hydrogen or - represent straight or branched alkyl, alkythyl, alkenyl or alkynyl containing in each case a maximum number of 12 carbon atoms which are optionally substituted by halogen, azido, imino, imino substituted by hydroxy, hydroxy, cyano, cycloalkyl containing 3 to 8 carbon atoms, or by a saturated or unsaturated trigonal and heptagonal heterocyclic radical containing a maximum number of 4 heteroatoms of the group consisting of nitrogen, sulfur and oxygen, or by aryl or aryloxy containing 6 to 10 carbon atoms, which in turn may be monosubstituted or tri-substituted by identical or different substituents selected from of the group consisting of halogen, nitro, phenyl, phenoxy, cyano, straight or branched chain alkyl, alkoxy or alkoxycarbonyl each containing up to 8 carbon atoms or a radical of formula ula 0 H ||

Or by a group of the formula -NR1 R2, COR2 or -OR1, wherein R3 and R4 are identical or different and each represents hydrogen, straight or branched chain alkyl containing a maximum number of 10 carbon atoms, or aryl containing

9D10 or branched ring containing up to 10 carbon atoms, phenoxy, aryl containing 6 to 10 carbon atoms or the group

-NR 9 R 9, wherein R 9 and R 9 have the abovementioned meaning,

R 2 represents hydrogen, cycloalkyl containing 3 to 8 carbon atoms, formyl, acyl containing up to 8 carbon atoms, tetrahydropyranyl, trifluoromethoxy or a group of the formula -SO 2 J 2 R 2, where p denotes an integer of 1 to 2, 13 R - is straight-chain or branched alkyl containing up to 8 carbon atoms or the group -NR R, where R and R are as defined above, or R represents straight chain or branched alkyl or alkenyl having up to 10 carbon atoms, which is optionally substituted by hydroxy, halogen, cycloalkyl containing 3 to 8 carbon atoms, alkoxy or alkoxycarbonyl containing up to 8 atoms of carbon, or by aryl containing 6 to 10 carbon atoms, which in turn may be substituted by halogen, hydroxy, alkyl, alkoxy or alkoxycarbonyl, each containing at most 8 carbon atoms, or nitro or ci or by a saturated or unsaturated 3 to 7 ring heterocyclic radical containing up to 4 hetero atoms selected from the group consisting of sulfur, oxygen, and -

or by a group of the formula -NR1 R2, -COR or -OR9 in which R1 to R2 have the meanings given above, or is substituted by a radical of the formula

N,

, C oder HoC

or represents aryl containing 6 to 10 carbon atoms, which is optionally substituted by halogen, hydroxy, nitro or cyano, or X is the same or different and each represents - halo, cyano, hydroxy or nitro, - represent a heterocyclic radical having 3 to 7 ring atoms containing up to 4 hetero atoms selected from the group consisting of sulfur, oxygen and nitrogen or pyridyl-3-methoxy, or - represent aryl containing 6 to 10 carbon atoms , which in turn may be substituted by halogen, cyano, phenyl, nitro, straight or branched chain alkyl or alkoxy, each containing up to 8 carbon atoms, or hydroxyl, or - containing 3 to 8 carbon atoms, represent a group of the formula -NR1 R2, -COR or -OR9, wherein R1 to R2 have the meanings given above, or R1 and R2, R2 and R3, R 3 and R 4, R 5 and R 6, R 6 and R 7, or R 7 and R 8, in each case, together with a saturated or unsaturated pentene and heptagonal carbocyclic radical optionally substituted by nitro, cyano, hydroxy, straight or branched chain alkyl having up to 8 carbon atoms, or a group of the formula - NR 1, R 2, -COR, or -OR, wherein R 1 to R 2 have the abovementioned meanings,

Ra and Rx are the same or different and in each case - represent hydrogen, or straight or branched chain alkyl containing up to 10 carbon atoms, which is optionally substituted by halogen, nitro, cyano, hydroxy or a wherein R 1 and R 2 have the abovementioned meanings, - represent aryl containing 6 to 10 carbon atoms, optionally substituted by nitro, cyano, halogen, alkyl, alkoxy or alkoxycarbonyl containing a maximum number of 8 carbon atoms or a group of the formula -NR10 R9, wherein R5 and R8 have the abovementioned meanings.

or R 14 and R 5 together form a saturated or unsaturated pentagonal and heptatonic carbocyclic radical and refers to its physiologically acceptable salts.

It has been found that the compounds according to the present invention exert an antihypertensive action and strongly stimulate the release of ANP, so they are suitable for the control of hypertonia and in case of intoxications by digitalis preparations, and well thus are suitable for the treatment of heart failure, cardiac dysrhythmias and edema.

Preferably, the physiologically acceptable acid addition salts of the compounds of formula (I), as well as the racemic forms, antipodes and diastereomeric mixtures, are also suitable for this new application.

Preferred compounds of general formula (I) are those in which R¹² to R² are identical or different and in each case - represent hydrogen or - represent straight or branched alkyl, alkylthio, alkenyl or alkynyl containing, in particular, each case, up to 10 carbon atoms, which are optionally monosubstituted and are unsubstituted or substituted by identical or different radicals selected from the group consisting of hydroxy, hydroxy, hydroxyl, fluoro, chloro, bromo, azido, imino, , cyano, cyclopropyl, cyclopentyl, cyclohexyl, or by pyrryl, morpholino, piperidyl, oxiranyl or by phenyl which in turn may be mono-substituted with tri-substituted by identical or different substituents selected from the group consisting of fluorine , chlorine, bromine, iodine, nitro, phenyl, phenoxy, straight or branched chain cyano, alkoxy or alkoxycarbonyl groups each containing up to 6 carbon atoms or a radical of formula or are substituted by a group of the formula -NR1 R2, -COR3, or -OR, wherein R6 and R7 are identical or different and in each case signify hydrogen, straight-chain alkyl or branched chain containing up to 8 carbon atoms, or phenyl, or a group of the formula -S (O) R 5

R 3 represents hydrogen, hydroxy, straight or branched chain alkyl or alkoxy containing up to 8 atoms. R 9 is hydrogen, cyclopropyl, cyclobutyl, cyclopentyl, cycloheptyl, cycloheptyl, formyl, acyl containing cyclohexyl, cyclohexyl, cyclohexyl, cyclohexyl, cyclohexyl, cyclohexyl, cyclohexyl, cyclohexyl, cyclohexyl, cyclohexyl, cyclohexyl, cyclohexyl, a maximum number of 6 carbon atoms, tetrahydropyranyl, tri-fluoromethoxy or a group of the formula -S (O) -R, wherein rp signifies an integer from 1 to 2.13 R- means straight or branched chain alkyl, containing a maximum of 6 carbon atoms or the group -NR1 R2 in which R1 and R2 have the abovementioned meanings, 3 or 4, R4 represents straight or branched chain alkyl or alkenyl, containing a which is optionally monosubstituted to tetra-substituted by identical or different radicals selected from the group consisting of hydroxy, fluoro, chloro, bromo, cyclopropyl, cyclopentyl, cyclohexyl, alkoxy or alkoxycarbonyl, containing a number bad-

with up to 6 carbon atoms, or by phenyl, which in turn may be substituted by fluorine, chlorine, bromine, hydroxy, alkyl, alkoxy or alkoxycarbonyl, each containing up to 6 carbon atoms , nitro or cyano, or is substituted by oxiranyl, pyrimidyl, pyridyl or by a group of the formula -NR 9 R 10, -COR 11 or -OR 12, wherein R 1 to R 2 have the abovementioned meanings, or is substituted by a radical of formula i

H

O

OR 1 8 R a R are identical or different and in each case. are fluorine, chlorine, bromine, iodine, cyano, hydroxy, nitro or pyridyl-3-methoxy, pyridyl, furyl, thienyl, 2,3-dihydrofuranyl, dihydropyranyl or thiazolyl, oxiranyl or phenyl which are optionally substituted by fluorine , chlorine, bromine, phenyl, straight or branched chain alkyl or alkoxy containing up to 6 carbon atoms, or hydroxy, or - represent cyclobutenyl, cyclopentenyl or cyclohexenyl, - represents a group of the formula -NR1 R2, -COR or -OR1, wherein R1 to R2 have the abovementioned meanings, or R1 and R2, R2 and R3, R3 and R4, R5 and R6, R6 and R7, or R7 and R8 together represent phenyl, cyclopentyl or cyclohexyl e. R14 and R15 are identical or different and. in each case,

- represent hydrogen, or straight-chain or branched alkyl having up to 8 carbon atoms, which is optionally substituted by fluorine, chlorine, bromine, cyano, hydroxy or a group of the formula -NR1 R2, -OR 9, wherein R a and R have the abovementioned meanings, or represent phenyl, optionally substituted by nitro, cyano, fluoro, chloro, bromo, alkyl, alkoxy or alkoxycarbonyl containing up to 6 atoms or by the group of the formula -NRR, where R and R are as defined above, and refers to the physiologically acceptable salts thereof.

Compounds of general formula (I) which may be mentioned in an especially preferred manner are those in which R 1 to R 8 are identical or different and in each case - represent hydrogen or - represent straight chain alkyl, alkylthio, alkenyl or alkynyl or branched, in each case containing up to 8 carbon atoms which are optionally monosubstituted and tetra-substituted by identical or different radicals selected from the group consisting of fluoro, chloro, bromo, iodo, azido, imino, iodo substituted by hydroxy, hydroxyl, cyclopropyl, cyclopentyl, cyclohexyl, or are substituted by morpholino, piperidyl, pyrryl, oxiranyl or phenyl, which in turn may be mono-substituted with tri-substituted by identical substituents or different selected from the group consisting of fluorine, chlorine, phenyl, phenoxy or by straight or branched chain alkyl or alkoxy containing up to 4 carbon atoms, or are substituted by by a radical of formula

Or by a group of the formula -NR1 R2, -COR or -OR, in which R6 and R6 are identical or different and in each case represent hydrogen, straight-chain or branched alkyl containing up to 6 carbon atoms or phenyl or by a group of the formula -S (O) -R, R1 is hydrogen, hydroxy, trifluoromethyl, alkyl or alkoxy of the chain linear or branched alkyl group containing up to 6 carbon atoms, phenoxy, phenyl or the group --NR 9 R 10, where R and R are as defined above, R 12 represents hydrogen, cyclopropyl, cyclopentyl, cycloheptyl, formyl, acyl containing up to 4 carbon atoms, tetrahydropyranyl, trifluoromethyl or a group of the formula -S (Q) R, wherein p represents an integer r of 1 to 2, straight chain or branched alkyl having up to 4 carbon atoms, or represents alkyl or alkenyl of ailinear or branched alkyl having up to 6 carbon atoms which is optionally monosubstituted and trisubstituted by identical or different radicals selected from the group consisting of hydroxy, fluoro, chloro, bromo, cyclopropyl, cyclopentyl, cyclohexyl, alkoxy or alkoxycarbonyl group containing up to 4 carbon atoms or by phenyl, which in turn may be substituted by fluorine, chlorine, hydroxy, or alkoxy containing up to 4 carbon atoms, or is substituted by oxiranyl or a group of the formula -NRâ, ... Râ, ... Râ,, - CORâ,, wherein Râ, â, ... Râ,, are as defined above, or is substituted by a radical of formula

H || 0 or 18 are identical or different and in each case represent fluorine, chlorine, bromine, iodine, hydroxy or nitro, pyridyl-3-methoxy, or represent furyl, pyridyl, 2,3-dihi -phenyl or oxiranyl, which, in turn, may be substituted by fluorine, chlorine, methyl, isopropyl, phenyl or ethoxy, represent a group of the formula -NR1 R2, COR or -OR, wherein R 1 and R 2 have the abovementioned meanings, R 1 and R 2 are identical or different and represent hydrogen, straight or branched chain alkyl containing up to 6 carbon atoms, or phenyl . -13-

The present invention relates in particular to novel compounds of general formula (Ia)

(Ia) in which R 1 to R 2 are identical or different and in each case - represent hydrogen or - represent straight or branched alkyl, alkylthio, alkenyl or alkynyl containing in each case a maximum number of Carbon atoms which are optionally substituted by halogen, azido, imino, imino substituted by hydroxy, hydroxy, cyano, cycloalkyl containing 3 to 8 carbon atoms, or by a saturated or unsaturated trigonal to heptagonal heterocyclic radical containing a maximum number of 4 heteroatoms in the group consisting of nitrogen, sulfur and oxygen, or by aryl or aryloxy containing 6 to 10 carbon atoms, which in turn may be monosubstituted or tri-substituted by substituents which may be identical or different, selected from the group consisting of halogen, nitro, phenyl, phenoxy, cyano, straight or branched chain alkyl, alkoxy or alkoxycarbonyl, each containing up to 8 carbon atoms or radic al of formula: or by a group of the formula -NR1 R2, -COR or -OR, wherein R6 and R6 are identical or different and each represents hydrogen, linear or branched, containing up to 10 carbon atoms, or aryl containing 6 to 10 carbon atoms or a group of the formula -S (O) p R13, R is hydrogen, hydroxy, alkyl or alkoxy, straight chain or branched ring containing up to 10 carbon atoms, phenoxy, aryl containing 6 to 10 carbon atoms or the group -NR RR ,R,, wherein R R and R têm have the abovementioned meaning, R ^ representa represents hydrogen, cycloalkyl containing 3 to 8 carbon atoms, formyl, acyl containing up to 8 carbon atoms, tetrahydropyranyl, trifluoromethoxy or a group of the formula -S (O) R, wherein

R p represents an integer of 1 to 2, R 2 represents straight or branched chain alkyl containing up to 8 carbon atoms or the group -NR 3 R 2, wherein R 1 and R 2 have the abovementioned meaning , or R 2 represents straight or branched chain alkyl or alkenyl containing up to 10 carbon atoms, which is optionally substituted by hydroxy, halogen, cycloalkyl containing 3 to 8 carbon atoms, alkoxy or alkoxycarbonyl containing a number of 3 carbon atoms, or by aryl containing 6 to 10 carbon atoms, which in turn may be substituted by halogen, hydroxy, alkyl, alkoxy or alkoxycarbonyl, each containing a maximum number of C 8 -C 8 -alkyl, or nitro or cyano, or by a saturated or unsaturated 3 to 7 ring heterocyclic radical containing up to 4 hetero atoms selected from the group consisting of sulfur, oxygen and nitrogen, or by a group of f wherein R 1 to R 2 has the meanings given above, or is substituted by a radical of the formula H? 0

or is aryl containing 6 to 10 carbon atoms, which is optionally substituted by halogen, hydroxy, nitro or cyano, or R8 is the same or different and in each case - represents halogen, cyano, hydroxy, or nitro - represent a heterocyclic radical having 3 to 7 ring atoms, containing up to 4 heteroatoms selected from the group consisting of sulfur, oxygen and nitrogen or pyrid-3-methoxy, or - represent aryl containing 6 to 10 carbon atoms, which in turn may be substituted by halogen, cyano, phenyl, nitro, straight or branched chain alkyl or alkoxy,

containing in each case up to 8 carbon atoms, or hydroxyl, or - represent cycloalkenyl containing 3 to 8 carbon atoms, represent a group of the formula -NR1 R2, -COR or -OR, In which R 1 and R 2 have the abovementioned meanings, or R 1 and R 2, R 2 and R 2, R 2, R 3 and R 4 are each independently selected from the group consisting of a saturated heptatonic and pentagonal carbocyclic radical or unsaturated, optionally substituted by nitro, cyano, hydroxy, straight or branched chain alkyl having up to 8 carbon atoms, or by a group of the formula -NR1 R2 R3, Wherein R 1 to R 2 have the abovementioned meanings, R 1 and R 2 are identical or different and in each case represent hydrogen, or straight-chain or branched alkyl containing up to 10 atoms of carbon, which is optionally substituted by halogen, nitro, cyano, hydroxy or a group of the formula -NR1 R2, -COR or -OR9, wherein R 2 to R 3 have the abovementioned meanings, - represent aryl containing 6 to 10 carbon atoms, optionally substituted by nitro, cyano, halogen, alkyl, alkoxy or alkoxycarbonyl containing up to 8 carbon atoms or group of the formula -NR R 9, wherein R and R have the abovementioned meanings, or R and R together form a 5- to 5-membered saturated or unsaturated carbocyclic radical, wherein, a) R can not represent hydroxyl, methoxy or acetyl groups, if 1,345,734,15 R represents methoxy, R, R, R, R, R and R are each hydrogen, R is methyl and R represents the group or b) R and R may not represent bromine and R may not react 1 3 4 14 15

R 2, R 2, R 2 and R 3 are hydrogen, R 2 is methoxy, R 1, R 2, R 3 and R 4 are hydrogen,

or c) R may not be methoxy, if R is methoxy, R 2, R 3, R 4, R 5 and R 4 are hydrogen, R 2 represents methoxy and R 2 is

or d) can not represent methoxy, if R 1, R 2 and R x are hydrogen and R x is the group of formula

The novel compounds of formula (I) and formula (Ia) according to the present invention have an unexpected and useful spectrum of pharmacological actions. They influence the release of ANP, the contractility of the heart, the tonicity of smooth muscle and the balance of electrolytes and body fluids, and, in addition, dissolve, either partially or totally, as antagonists or agonists of the digitalis preparations .

Thus, these compounds may be employed in medicaments for controlling pathologically elevated blood pressure, in particular in the form of antihypertensive preparations, for the treatment of heart failure as well as therapeutic agents for coronary affections or as a drug in cases of prepared digitalis.

In addition, these compounds may be used in the treatment of cardiac dysrhythmias, renal failure, hepatic cirrhosis, ascites, pulmonary edema, cerebral edema, pregnancy edema or glaucoma.

The compounds of formula (I) and (Ia) according to the present invention exist in stereoisomeric forms, which behave as the image of each other in a flat mirror (enantiomers) or which are not the image of one another in a flat mirror (diastereomers). The present invention relates to both antipodes and racemic forms, and to diastereomeric mixtures. Racemic forms such as diastereomers can be separated in known manner into the stereoisomerically pure or uniform components (see E. L. Eliel, Stereochemistry of Carbon Compounds, McGraw Hill, 1962).

The physiologically acceptable salts may be salts of the compounds of general formula (I) and (Ia) according to the invention with inorganic or organic acids. Such as, for example, hydrochloric acid, hydrobromic acid, phosphoric acid or sulfuric acid, or salts with organic sulfonic or carboxylic acids, such as, for example, acetic acid, maleic acid, fumaric acid, malic acid, citric acid, tartaric acid, lactic acid, benzoic acid, or methanesulfonic acid, ethanesulfonic acid, phenylsulfonic acid, toluenesulfonic acid or naphthalenedisulfonic acid.

The compounds of general formula (I) or (la) according to the present invention may be prepared by a process, characterized in that compounds of general formula (II)

wherein R4 and R4 are as defined above, X1 represents fluoro, chloro, bromo or iodo, and Y2 represents (C1 -C6) -alkoxy or aryloxy of 6 to 10 carbon atoms, are condensed to compounds of general formula (III)

R1 &lt; ks / 0-Z (III) &gt; 8. Wherein R3 to R4, Rx and Rx have the abovementioned meanings, and Z represents a typical hydroxy protecting group, such as, for example, tetrahydropyranyl, or compounds of general formula (IIa)

(IIa) in which R 1, R 4 and R 4 have the abovementioned meanings, are condensed with compounds of general formula (IIIa)

in which R 5, R 5, R 1, X and Z have the abovementioned meanings, in inert solvents, with the elimination of halides, such as, for example, hydrogen bromide, to give general formula (IV)

(IV) wherein R 1, R 2, R 3, R 4, Y and Z have the abovementioned meanings and then the hydroxy group is unblocked by the usual methods and the compounds are cyclized with water elimination,

(III) and (IIIa), both before condensation, and after cyclization of the compounds of formula (II), (IIa), (IIIa) and (IIIa) can be introduced. (IV) by known methods, such as, for example, alkylation, acylation, substitution, addition, elimination, rearrangement, oxidation, radicalisation or reduction and, if appropriate, other functional groups, or characterized in that [S], starting from the natural substance of formula (Ib)

(Ib) (hereinafter &quot; penicillide &quot;) wherein R 1 is methoxy, 2 'R is

OH

6 'is methyl and 8', R is hydroxy, 10 g the substituents R 1 to 8, R 'and R' are each introduced by the usual methods of the process / A 7 ', and given hereinafter by way of example, such as , for example, rearranging, alkylation, acylation, addition, elimination, oxidation, radical reaction or reduction in inert solvents, if appropriate, in the presence of auxiliary agents such as, for example, bases, acids , catalysts or activating reagents, and converting these substituents, as well as the substituents R 1, R 2, R 3, R 4 and R 5 into other functional groups. (a) The natural substance of formula (Ib) or suitable derivatives which have been prepared by the method described in process 7 are reacted one or more times with compounds of general formula (V)

(V) wherein R corresponds to the scope of meaning of one of the above R 1 -R substituents but does not represent hydrogen, and D represents a leaving group such as, for example, chlorine, bromine, iodine In suitable solvents, in the presence of auxiliary agents such as, for example, bases, acids or catalysts, or (b) compounds of formula (Ib) or suitable derivatives, for example, with amines, hydrazoic acid and ethyl azodicarboxylate, acetic acid, acetic anhydride, tetrahydropyranyl, thionyl chloride, methanesulfanyl chloride,

2-pyrrolidone-5-carboxylic acid and hydroxylamine in inert solvents and, if appropriate, in the presence of auxiliary agents such as bases or catalysts, or c) reacted with Grignard reagents of general formula (VI) (VII) wherein R 1 and R 2 have the meaning given above, in inert solvents, or d) are halogenated with compounds of general formula (VII) wherein

Hal represents fluorine, chlorine, bromine or iodine and represents one of the abovementioned R 5 substituents R 5, with the meaning of fluorine, chlorine, bromine or iodine, or represents the radical -CH 2 -NC 3 in inert solvents and, if appropriate, then double bonds are introduced by elimination reactions according to known methods and, if appropriate, epoxidation is carried out and, if appropriate, then a reduction, oxidation or hydrolysis, according to usual procedures, whereby the RR substituents are introduced into the compounds of general formula (Ib) and the appropriate derivatives, R 2, R 2, R 3 and R 4 are as defined above.

Depending on the type of starting materials used, the synthetic variants for the compounds according to the present invention may be represented by the following equations: CA3 H,

j + H 3 Cl-MgBr, THF, ether

, COOO H, THF H 'OH

+ LiOH, THF 26-

ch3cn

The

(C 2 H 5) 2: i) sodium iodide

+ [Ph 3 P CH 3] 0CBr 30 / LiNH 2 -27-

1.) 1 9-DBN 2) NaOH / H2 O2

or

NaBH4, THF or

OH

NaCNBH 3, THF, CH 2 COOH

HgCOâ, "Vâ,,CHâ,,

Processes ÇhJ - Ç &amp;]

Solvents for the processes &lt; 7 &gt; 7, which may be employed in the present case, are the usual organic solvents which do not change under the reaction conditions. Preferably, such solvents include alcohols, such as methanol, ethanol, propanol or isopropanol, or ethers, such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or glycol butyl methyl ether, or ketones, such as acetone or butanone , or amides, such as dimethylformamide or hexamethylphosphoramide, or carboxylic acids, such as acetic acid or propionic acid, or dimethyl sulfoxide, acetonitrile, ethyl acetate, or halogenated hydrocarbons such as methylene chloride, chloroform or tetrachloride carbon, or pyridine, picoline or M-methylpiperidine. Mixtures of said solvents may also be used. 30-

In all processes, the reaction temperatures may vary over a wide range of temperatures. Generally, the reactions will be carried out between -20 ° C and + 2003 ° C, preferably between +2 ° C and + 100 ° C, in particular at the boiling point of the respective solvent used.

The reactions may be carried out at normal pressure, but may also be carried out at a reduced or elevated pressure. Generally, the reaction will be carried out at normal pressure.

In carrying out variants A and B of the process of the invention, the proportions of the substances used for the reaction do not constitute fixed quantities. However, in general, the reaction will be carried out with equimolar amounts of the reactants. Preferably, the isolation and purification of the substances according to the present invention are carried out in such a way that the solvent is removed by distillation in a vacuum, and the residue, which can be obtained only in the crystalline form after the cooling with ice, is recrystallized from an appropriate solvent. In some cases, it may become necessary to purify the compounds of the invention by chromatography.

Suitable bases are the usual inorganic or organic bases. These bases preferably include alkali metal hydroxides, such as, for example, sodium hydroxide, lithium hydroxide or potassium hydroxide, or alkali metal carbonates, such as sodium carbonate or potassium carbonate, or alkoxides of alkali metals, such as, for example, sodium methoxide, or potassium methoxide, or sodium ethoxide or potassium ethoxide, or organic amines, such as triethylamine, picoline or N-methyl piperidine, or 2-chloroiodide -N-methylpyridonium, or amides, such as sodium amide, lithium amide, lithium diisopropylamide or organometallic compounds such as lithium propylate or lithium phenylate.

Catalysts which may be used for the different variants of the process of the invention are, for example, copper salts or oxides, preferably copper (II) acetate and copper or alkali metal iodides such as sodium or potassium iodide, which are added to the reaction mixture in a proportion of from 0.5 to 150 equimolar units, preferably from 5 to 50 equimolar units.

Additive activating reagents are, for example, azo-dicarboxylic acids or tri-phenylphosphine, either at molar or excess ratios. The condensation reaction reported in the process is carried out in one of the solvents mentioned above with the addition of a base, preferably in pyridine with potassium carbonate, while for the cyclization preferably acetonitrile, triethylamine and iodide of 2-chloro-N-methylpyridinium bromide.

The auxiliary agents which are employed are preferably condensing agents, especially if the carboxyl group is present in the activated form of the anhydride. In this case the usual condensing agents, such as carbodiimides, eg N, N'-diethyl-, N, N'-dipropyl-, N, N-diisopropyl- or N-dicyclohexylcarbodiimide, hydrochloride of N- (3-dimethylaminesopropyl) -N'-ethylcarbodiimide or 2-chloro-N-methyl-pyridinium iodide. The introduction and removal of the hydroxy protecting group is carried out by customary methods (Th. Greene, Protective Groups in Organic Synthesis, Ist Edition, J.

Wiley &amp; Sons, New York, 1981). The protecting groups may be removed, for example by means of hydrogenolysis or acidic or basic hydrolysis.

The alkylation is carried out in one of the abovementioned inert solvents, preferably in dimethylstannamide, in the presence of potassium carbonate.

The reduction is generally carried out with metal hydrides or borohydrides of metals which are preferably sodium borohydride and sodium cyanoboridehydride in inert solvents, such as ethers, preferably in tetrahydrofuran, diethyl ether or dioxane, in a solvent. temperature range between -20 ° C and -5-100 ° C, preferably between 0 ° C and + 50 ° C, at normal pressure.

In addition, the reduction may further be carried out by hydrogenation in inert solvents such as alcohols, eg, methanol, ethanol, propanol or isopropanol, in the presence of a noble metal as a catalyst, such as platinum, palladium, palladium-on-charcoal or Raney nickel in a temperature range of from 0Â ° C to + 150Â ° C, preferably from room temperature to + 10Â ° C, at normal pressure or at a higher pressure. Reduction of the carbonyl groups to hydrocarbons generally takes place using reducing agents such as zinc and acid amalgam such as hydrochloric acid or using hydrazine hydrate and bases such as sodium hydroxide or potassium hydroxide in the above solvents, preferably in ethers, such as tetrahydrofuran or diethyl ether. Generally aldoximes and ketoximes are reduced to the corresponding amines using said metal hydrides, preferably using lithium aluminum hydride, or zinc and acetic acid, boric acid, sodium in alcohols, or are reduced by catalytic hydrogenation back mentioned.

In general, the reduction of the alkoxycarbonyl groups to alcohol groups is carried out with the aid of hydrides, preferably using aluminum-

in inert solvents such as ethers, hydrocarbons or halogenated hydrocarbons or mixtures thereof, preferably in ethers, such as, for example, diethyl ether, tetrahydrofuran or dioxane, in a temperature range between 02C and + 150Â ° C, preferably between + 20Â ° C and + 100Â ° C, at normal pressure. Oxidation of alcohols to form aldehydes and ketones is generally carried out using oxidizing agents such as dichromate, potassium permanganate, bromine, manganese dioxane, dipyridine-chromium (VI) oxide, pyridine dichromate , a dimethyl pyrazole-CrO 2 complex, silver carbonate on Celite, iodoso-benzene, lead tetra-acetate-pyridine, pyridinium chlorochromate or the Jones reagent, preferably using pyridinium chlorochromate in the solvents above, preferably in a temperature range between -20 ° C and + 100 ° C, preferably between OSC and + 50 ° C, under normal pressure.

Generally Wittig reactions are carried out by reaction with tetraalkyl or aryl substituted phosphonium halides, preferably using triphenylmethylphosphonium bromide, in inert solvents such as ethers, preferably tetrahydrofuran, in the presence of a base , preferably lithium amide, in a temperature range between -10 ° C and + 100 ° C, preferably at room temperature, and at normal pressure.

Generally, the substitution reaction is carried out in the foregoing inert solvents or in water, preferably in water, formic acid, methanol, ethanol, dimethylformamide or in mixtures of such solvents and, if appropriate, in the presence of one of the bases mentioned above or in said catalysts, in a temperature range between -60Â ° C and + 200Â ° C, preferably between 0Â ° C and + 100Â ° C and normal pressure. The halogenation is carried out in one of the above inert solvents, preferably dimethyl-

formamide in a temperature range of -10Â ° C to + 150Â ° C, preferably between + 25Â ° C and + 80Â ° C, at normal pressure.

Reactions which are not indicated in detail and which are intended for the introduction of R 1 to R substituents, such as, for example, acylations, nucleophile or electrophilic substitutions, radical reactions, deletions and rearrangements, are carried out by methods known in the art literature / cf. for example C. Ferri, Reaktionen der organischen Synthesis (reactions of Organic Synthesis),

Georg Thieme Verlag, Stuttgart 1978 and J. March, Advanced Organic Cheraistry, second edition, McGraw Hill Book Company.

The compounds of the general formulas (II), (IIa), (III), (IIIa), and (IV) are known per se or can be prepared by the usual methods of Tietze and Eicher, Reaktionen und Synthesen im organisch chemischen Praktikum Reactions and Syntheses in Organic Chemical Practice), Georg Thieme Verlag, Stuttgart, New York, 1981; W. Fuerer, H. W. Gschwend, J. Org. Chem. 4, 1133-1136 (1979); F. W. Vierhapper E. Trengler, K. Kratzal, Monatshefte fur Chemie, 106, 1191-1201 (1975); Jonh A. Elix and Vilas Jayanthi, Aust. J. Chem. 1987, 40, 1841-18507.

The compounds of formula (Ib) can not be prepared according to the disclosure in Tetrahedron Letters, 45, pp. 3941-3947, (1974). However, it was possible to isolate them by standard methods with the aid of the new strain Penicillium funiculosum Thom / cf. Boden-waschtechnik zur Isolierung von Boden- und Risksparenpilzen, Methoden des mykologischen Laboratoriums (Soil washing techni-which for isolation of fungi which live in the soil and rhizos-phere, Mycological Laboratory Methods), H. Kreisel, F. Schauer Gustav Fischer Verlag , Stuttgart, New York, 19877 * A culture of this strain was deposited in the German collection of Microorganisms in Braunschweig, 08-03-1989, under registration number DMS.5249.

The compounds of formula (V), (VI) and (VII) are known or may be prepared by known methods / eg, J. March, &quot; Advanced Organic Chemistry &quot;, Second edition.

The novel compounds and compounds of formula (I) and (Ia) already known have a novel and useful spectrum of pharmacological action. These compounds can influence the release of ANP, the contractility of the heart, the smooth muscle tone and the balance of electrolytes and fluids, and act either partially or totally, as digitalis antagonists or as digitalis agonists.

Accordingly, they may be used in medicaments for the treatment of pathologically altered blood pressure or in the treatment of heart failure, and as coronary drugs or coronary agents or therapeutic agents in digital envenomation.

In addition, they can be used in the treatment of cardiac dysphythia, renal failure, cirrhosis of the liver, ascites, pulmonary edema, cerebral edema, edema of pregnancy or glaucoma. The antihypertensive action of 3- (1-hydroxy-3-methylbutyl) -4,11-dimethoxy-9-methyl-7H-dibenzo-5 / dioxocin-5one was studied in rats suffering from hypertonia due to &quot; reduced renal mass &quot;. Reduced renal mass (RRH) hypertonicity was induced by the removal of 5/6 renal mass (nephrectomy), with 0.5% saline solution instead of drinking water, based on in the method described by von Hvart et al. (1983). The compound of example 39 showed, in this hypertonic form, a DE 2 q (reactance of 20%

systolic blood pressure after indirect measurement in conscious rats) of 100 mg / kg.

In turn, the compounds of examples 12, 34, 74, and 76 stimulate the release of ANP at 292, 265, 196 and 192%, to the isolated auricle of the rat. The concentration of ANP in the bath fluid was determined by radioimmunoassay [δ. P. Stasch, H. Grote, S. Kazda, C. Hirth, Dynorphin stimulates the release of ANP from isolated rat, Eur. J. Pharmacol. 159, 101 (1989) J.

The novel active compounds can be converted in known manner into the usual pharmaceutical formulations, such as tablets, dragees, pills, granules, aerosols, syrups, emulsions, suspensions and solutions, using in their preparation inert, non- toxic, pharmaceutically acceptable salts. In this context, the active compound should be present - in each case - in a concentration of about 0.5 to 90%, by weight, relative to the total mixture, i.e. in amounts sufficient to reach the stated dosage range.

The formulations are prepared, for example, by diluting the active compounds with solvents and / or excipients and, if appropriate, using emulsifiers and / or dispersants, which may be used - for example, if water is used as diluent - organic solvents as auxiliary solvents if appropriate.

Auxiliary solvents which may be mentioned are, for example, water, non-toxic organic solvents, such as paraffins (eg, mineral oil fractions), vegetable oils (eg, sesame oil / sesame oil), (e.g., ethyl alcohol, glycerol), excipients, such as, for example, crushed natural minerals (eg, calumines, alumina, talc, chalks), crushed synthetic minerals (eg, highly silicates), sugars (for example,

emulsifiers (eg esters of polyethylene fatty acids, ethers of polyoxyethylene fatty alcohols, alkyl sulphonates, aryl sulphonates), and detergents, eg lignin, water sulphites, methylcellulose, starch and polyvinylpyrrolidone) and lubricants (eg, magnesium stearate, talc, stearic acid and sodium lauryl sulfate). Administration of the formulations is carried out in the usual manner, preferably orally or parenterally, especially perlingually or intravenously. In the case of oral administration, the tablets may contain - in addition to said excipients - still additives such as sodium citrate, calcium carbonate and di-calcium phosphate together with various other adjuvants, such as starches, preferably potato starch, gelatin and the like. In addition, lubricants, such as magnesium stearate, sodium lauryl sulfate and talc, may still be used for the preparation of tablets. In the case of aqueous suspensions, various flavorings or dyes may be added to the active compounds, in addition to said auxiliary agents.

In the case of administration, solutions of the active compounds may be used, using appropriate liquid excipients.

In general, it has been found to be advantageous - in the case of intravenous administration, to administer amounts of about 0.001 to 1 mg / kg, preferably 0.01 to 0.5 mg / kg of body weight, in order to achieve and for oral administration the dosage may range from about 0.01 to 20 mg / kg, preferably from 0.1 to 10 mg / kg of body weight.

However, it may be necessary to depart from said proportions, which will depend in particular on the body weight or gender of the chosen route of administration, the individual response to the administered drug, the type of its formulation , and the height or time interval during which administration is effected. Thus, in some cases, it may be sufficient to administer less than the abovementioned minimum quantity, whereas in other cases, it may be necessary to exceed the maximum limit value indicated. In the case of administration of large amounts, it may be advisable to divide the amounts into several individual doses to be administered during the day. -39-

PREPARATION OF STARTING COMPOUNDS

EXAMPLE I 5-Formyl-2- (4-methoxy-6- (2-tetrahydropyranyloxymethyl) 7-phenoxy benzoate

8.2 g (34.6 mmol) of 2-methoxy-6- (2-tetrahydropyranyloxymethyl) phenol, 5.3 g (38 mmol) of potassium carbonate and 3.0 g (38 mmol) ) of copper oxide was added to a solution of methyl 2-bromo-5-dimethyl-xymethylbenzoate (10 g, 34.6 mmol) in 25 ml of absolute pyridine. The mixture is heated to 130Â ° C. After 3 hours, an additional 3.0 g (38 mmol) of copper oxide is added. After a reaction period of 12 hours, the solvent is removed by distillation, the residue is dissolved in dichloromethane and the mixture is extracted with dilute hydrochloric acid. The organic phase is washed with water, dried and evaporated in vacuo and the residue is purified by chromatography on a silica gel column using petroleum ether / ether (1: 1) as eluents. 40- MS (mass spectrum) EI (electron impact): 400, 315, 300, 255, 239

Yield: 6.5 / (48/6 theory). SF (molecular formula): C22 H24 O7: 400%

EXAMPLE II Methyl 5-formyl-2- [2-methoxy-4-methyl-6- (2-tetrahydropyranyloxymethyl) -3-phenoxybenzoate

The title compound was prepared according to the procedure reported in example I.

Yield: 78% of theory. MS: (EI): 414, 314, 269, 135: C23H2607 (414) -41-

EXAMPLE III Methyl 5-formyl-2- (6-hydroxymethyl-2-methoxy) phenoxybenzoate

100 mg (0.25 mmol) of the compound of Example I were dissolved in a mixture of 2 ml of acetic acid, 1 ml of tetrahydrofuran and 0.5 ml of water, and the mixture was heated to 50Â ° C for 4 hours . After a further 12 hours at ambient temperature the mixture is concentrated in vacuo and the residue is co-distilled 3 times with toluene and is purified by chromatography on a silica gel column using ether / ethyl acetate ( 2: 1) as eluents.

Yield: 60.5 mg (16% of theory). MS: (EI): 316, 255, 180, 148, 136 SP: C17H1606 (316)

The compounds in the following table 1 are prepared analogously to the procedure adopted in example III:

Ex. No,

IV

SAW

IX

(I.e.

(EI = impact (bombardment

SF

OH (CH3) 2 205

OH CHr

VII VIII

374, 239, 205, 255, 220, C21H266 (374) 346, 269, 239-285, 255, C19H226 (346) 360, 239, 255, 181 C20H246 (360) 408, 137-317, 6 (408) 394, 269, 317, 226, C23H226 (394) 428, 179, 351, 153, C23H21C106 (428) 388, 151-181, C22H286 (388)

X 43-

EXAMPLE XI

5-Formyl-2- (6-hydroxymethyl-2-methoxy) phenoxybenzoic acid

300 g (0.95 mmol) of the compound of Example 3 are dissolved in 15 ml of tetrahydrofuran, followed by the addition of 7.3 ml of a 0.2 N solution of lithium hydroxide in water. After 16 hours at 6 ° C, 6 ml of 32% hydrochloric acid is added to the solution. The substance begins to crystallize. After 2 hours, the precipitate is filtered off with suction, and the obtained residue is washed with a little water, after which it is dried over phosphorus pentoxide.

Yield: 192 mg (67% of theory). MS: EI: 302, 166, 148, 136 SP: C16H1406 (302)

The compounds shown in the following table 2 are prepared analogously to the procedure adopted in Example XI:

Ex. No. R2 R6 Formula SF (EI)

XII

OH H chcch 3) 2 OH H

XIII

XIV

XV

OH H

OH 360 360, 255, 167 342, 206, C20 H246 (360) 332, 137 167, C18H206 (332) 346, 149, 167, 137 C19H226 (346) 394, 303, 376, 137 C23H22O 6 (394) 380, 137227, C22H206 (380)

XVI

OH

H 414, 257, C 223 (414)

XVII

OH XVIII

CH3 374 &gt; 356 C21H26O6 206, 188 (374) 151

EXAMPLE XIX Methyl 5- (1-hydroxy-3-methylbutyl) -2- [5-methoxy-4-methyl-6- (2-tetrahydropyranyloxymethyl) 7-phenoxybenzoate

The title compound is obtained analogously to the procedure adopted in Example 140.

Yield: 50% of theory. MS (EI): 472, 327, 315, 285, 253 SF: C27H360; (472) -46

The compounds shown in following Table 2a were obtained analogously to the procedure of Example 140.

Table 2a

XX

XXI

XXII

OH

OH

OH / ch3 458, 313 C26H34O7 301,239, (458) CH 181 430, 344, C24H307, 301, 285, (430) CH3 239 DCI * 462 (M + NH4) * C25H32O7 444 , 427, (444): 2-ch2-ch3 361, 343

OH

XXIII

XXIV

DCI: 493 (M + H +), C oHo707 409, 334, (492) 7 316, 299 478, 393, C28H3007 333, 239 (478) 512, 394, C28H29C107 275 (512)

Cl

XXV

The compounds shown in Table 2b were prepared according to the procedure of Example I:

Table 2b:

Ex. R5 R7 R Formula SF N2. (HEY) '

XXVI

XXVII

XXVIII

(430) 414, 269, C23H2607 253, (414) 510, 508, C23H2gBr03 410, 408, (509) 378

XXIX

-CH 3 CH 3 CH 3 OCH 3 374, 324, C 2 O H 22 O 7 299, 256, (374)

The compounds shown in Table 2c were prepared according to the procedure of Example III:

Table 2c:

Ex. NS. (384) XXXII Br och3 484, 482 C22H27Br07 (483) C22H28O7 (484) C22H28O7 (484)

The compounds shown in Table 2d were prepared analogously to the procedure of Example 140.

Table 2d:

SF

XXXIV

XXXV

XXXVI

XXXIII

H 0 CH 3 488 j 347, 277 366 6 331, 299, (488) 269 ch3 h

(M + NH 4) +, (472) 455, 388, 371, 253 568, 566, c27H35Br08 425, 409, (567) 349

-CH 2 CH 3 CH 3 OCH 3 432, 375, C 24 H 39 O 4 326, 297, (432) 165-50-

EXAMPLE XXXVII

5- (1-Hydroxy-3-methylbutyl) -2- (6-hydroxymethyl-2-methoxy) phenoxy-6-methoxybenzoic acid

105 mg (0.26 mmol) of the compound of Example XXX are dissolved in 2 ml of methanol, whereupon 145 mg (2.6 mmol) of KOH is added. After 12 hours at ambient temperature the mixture is concentrated in vacuo, the residue is dissolved in water and the obtained mixture is acidified by the addition of dilute hydrochloric acid. The aqueous phase is extracted with CH2 Cl2 and the combined organic phases are dried over MgSO4 and concentrated in vacuo. The substance thus obtained is transformed without being characterized.

The compounds shown in Table 2e were prepared analogously to the procedure of Example XXXVII:

Table 2e

Ex. No. R5 R7 R Formula (EI) XXXVIII X0 (M X α 1 ch3 H 374 XXXIX -ch2oh Br och3 469 XL -ch-ch3 ch3 och3 418 OH

SF C21H26O6 (374) C21H25Br07 (469) C23H30O7 (418)

EXAMPLES OF CARRY-OUT EXAMPLE 1 3-Formyl-11-methoxy-7H-dibenzo [b, f] [1,5] dioxocin-5-rone

A solution of 180 mg (0.6 mmol) of the compound of Example XI and 663 μl (4.8 mmol) of triethylamine in 40 ml of absolute acetonitrile is added dropwise at 80 ° C to a solution of 609 mg (2.4 mmol) of 2-chloro-1-methylpyridinium iodide in 40 ml of absolute acetonitrile was added over a period of 6 hours. After a further 1 hour at 80 DEG C., the mixture is concentrated in vacuo, the residue is dissolved in dichloromethane, and the solution is washed with water, dried over magnesium sulfate and concentrated. Purification is performed by chromatography on a silica gel column using petroleum ether / ethyl acetate (4: 1). As the separation proceeds, it is changed to petroleum ether / ethyl acetate as the eluent system (1: 2).

Yield: 73 mg (43% of theory). MS: EI: 284, 239, 136 SF: C16H1205 (284)

The compounds; presented in the following table 3 were obtained analogously to the procedure of Example 1.

Table 3: 0

Ex. Formula (EI)

SF OH H 342, 285, C 20 H 22 5 11 149, 137, (342): CH 2 CH 3 CH 2 CH 3 CH 2 CH 3 285, C19H20O21, 137 (328) CH3 OH H 376, 285, C23H20O111 149, 137 (376) OH H 362, 283, C22H185117, 213 (362) 396, 139282, C22H17Cl (396)

CH, 356, 299 C21 H24 O5 (356)

EXAMPLE 9 3- (1-Hydroxy-3-methylbutyl) -11- (1-methylethoxy) -4-methoxy-9-methyl-7H-dibenzo [b, g], 5,7dioxocin-5-one

200 mg (0.54 mmol) of penicillide (1b) in 2 ml of dimethylformamide are stirred in an argon atmosphere at 25 ° C over a period of 12 hours with 0.5 ml (50 mmol ) of isopropyl iodide and 160 mg (1.14 mmol) of anhydrous potassium carbonate. After evaporation in vacuo, the residue is dissolved in 1N aqueous hydrochloric acid and the mixture is extracted exhaustively with diethyl ether. After drying the organic phase, the evaporation residue is chromatographed on silica gel, eluting with petroleum ether / ether (1: 1). The chromatographically pure fractions (TLC) are combined and evaporated.

Yield: 169 mg (72% of theory) of a colorless solid. MS (EI): 414, 357, 315, 297, 269, 243, 219 SF: C 24 H 30 O 6 (414)

The compounds shown in the following tables 4, 5, 6, 7 and 8 are prepared analogously to the procedure of Example 9.

Table 4

Ex. R12 Formula SF NQ. (EI) 10 - (CH2) 4-Br 508, 506, C25H31Br06 490, 488 (507) 451, 449 269, 137, 1351 DCI! 504, 486, C27 H34 O8 II 469, 448, (486) 11 -CH2-C-O-J-413 I-458, 401, C25H30-812 II -ch2-c-och2ch3 283, 255 (458) II 429, 372, C23H27N07 13 II -ch2-c-nh2 326, 274-297, (429) / ch3 428, 371, C25H32614 -CHO-CHNCH3 269, 243 (428) 476, 419, C29H326 15 -ch2-ch2-) 401, 105 (476) DCI + = desorption ionization of Oericae-

Continued from Table 4. R12

Formula SF (EI) 16

-CH- 18 - (CH 2) 5 -CH 3 CH 3

19 - (CH 2) 2 &quot; CH

NCH3 20 -CH2 -CH = CH3 21 -CH2 -CH2 -CH3 22 -CH2 &lt;] 23 -CH2 -CH3 462.9 91 405, C28H306 (462) 492, 315, 354, 269 C29H327 (492) 456 , 369, 269 399 353 C27H36O6 (456) 442, 357, 385, 339 C26H34O6 (442) 412, 309355, C24H286 (412) 414, 329, 357, 311 C24H306 (414) 426 , 269, 369, 179 C 25 H 30 ° 6 (426) 400, 313, 343, 297 C 23 H 28 O 6 (400) 428, 341, 371 335 C 24 H 28 O 7 (428)

24

Continued from Table 4

Ex. R12m. Formula (EI)

SF

25 -CH 2 -CH = CH

II 26 - (CH 2) 5-C-OCH 2 CH 3

27 - (CH 2) 6 -OH

288, 413 431, C30H326 (488) 514, 457, C29H388, 849, 297-427, (514) 472, 397 C27H367, 369, 297 (472) 430, 373, C 24 H 30 775, 337 343, (430) 440, 383, C26H326, 315, 269 (440) 454, 315, C27H346, 269, 219243, (454) 468, 411, C28H366, 468) 486, 471, C27H348, 429, 341, 353, 115 (486)

Continuation of table 4

Ex. R. 2 Formula SF NS. (HEY)

-CH

FAB: 614, 597, 269 C33 H42 O11 (614) 34 II - (CH2) 4 -O-C

H

DCI: 556, 462:: 423738, 444, C30H37N0 (555) 935 -CH2-CH = CH-CH3 426, 372, c25H306,

Table 5:

Ex. R12 / R12 Formula SF NS. (EI) 36 R12 = R12 '

= -CH

DCI: 445, 354, C3sH3606 298 (552) FAB ++ = Rapid atom bombardment

Continued from Table 5

Ex. R 12 / R 12 'Formula SF N 2. (HEY)

38 R12, = H R12 = 538 * 400, ^ 34 ^ 34 ^ 6 252, 168 (538) 460, 354, C25H32889 (460) -ch2o- (ch2) 2 -o3

-60- [χ. W 3 E M Ό Cm u ιη so (M co

K O fc

- - - - - - - - - - - - - - - - - - - - - - - - - - - - - (x, y) = X (x) = X (x) (x) (x) CO 2, X 2, X 2, X 2, X 2, X 2, X 2, X 2, X 2, X 2, X 2, X 2, X 2, X 2 X 2 X 2 X 2 X 2 X 2 X 2 X 2 X 2 X 2 X 2 X 1

X x X α x X u

Pi Xu

Irt X u u X XX xx

X X • · X 01. W. 2

Xo

Xo O Pi Ο -I TJ1 <0 · X X rr

Table 7 r12o

Ex. Formula gF NQ. (EI) 44

428, 371, C24 H287, 799, 269 (428)

45 -CH2 -CH2 -OH 416, 209-233 (28)

Table 8

Ex. R12m.

Formula (EI)

SF 46 -CH '

CH, FAB; 491 (M + H +) 154.12 C29 H30 O7 (490)

Table 8 continued 'EX. R12 NQ.

Formula SF (EI) -c 438, 370 C26H30647 150 (438) 48 -CH2 "XI 426, 151, 369, 132 C24H267 (426) 478, 476, C23H25Br06 49 -CH2 -CH2-Br 420, 353 418, CH3 412, 370 C24 H286, 650 -CH150 (412) 398, 341, C23H266, -CH2-CH3 312, 151-267 (398) -CH2-) 460, 403, C28H28 (410) -CH 2 &lt;] 424, 297, C25H28 ° 6, 543, 283, 269 (424). 484, 428, C27 H328, 838, 387, 327, (484), 552 (m)

(I.e.

Table 8 continued '

Ex. No. R12 Formula (EI) SF 56 -ch2-ch2-ch3 412, 312, 297, 151 C24H286 (412) 57 -CH2-CH2 -. 474, 432, 417, 370,150 C 29 H 30 ° 6 (474) 58 -ch- (c 6 H 5) 2 DCI: 554 (M + NH 4 +) 537, 453, 371, 167 C 34 H 32 O 6 (536) NCH 3 426, 370, 297, 151 C 25 H 30 ° 6 (426) 60 - (CH 2) 4 "Br 506, 504, 297, 177 C25H29O6Br0 II 448, 391, 283, 151 C22H248S (448) S-CH, O-CH2-C-NH2 427, 370, C23H25N02 2 312, 269-295, (447) ch3 484, 469, C27H328 -ch3 370, 269-353, (484) -CH.

EXAMPLE 64 3- (1-Acetoxy-3-methylbutyl) -11-methyl-7H-dibenzo [b, g] [1,4] dioxocin-5-one

O

100 mg (0.27 mmol) of penileilide (Ib) are stirred in 2 ml of pyridine and 1 ml of acetic anhydride for 14 hours at 25 ° C. The reaction mixture is evaporated in vacuo, the residue is dissolved in methylene chloride and the solution is washed with water. The evaporation residue of the dried organic phase is chromatographed (silica gel) using hexane / diethyl ether.

Yield: 61 mg (50% of theory) of a colorless solid. MS (EI); 456, 414, 354, 315, 298, 285, 269, 219

EXAMPLE 65 11-Hydroxy-4-methoxy-9-methyl-3- (3-methylbutan-1-onyl) -7H-dibenzo [p, g] [5,7] dioxocin-5-one och 30 0

800 mg (2.2 mmol) of penicillide (Ib) are stirred at 25 ° C in an argon atmosphere for 3 hours in 15 ml of methylene chloride and 880 mg (4.1 mmol) of pyridinium chlorochromate. After addition of 200 ml of diethyl ether, the mixture is filtered through Si60 silica gel. The evaporation residue of the filtrate is chromatographed on silica gel using ether (1: 1).

Yield: 363 mg (45% theory) of a colorless solid. MS (EI): 370, 313, 177 SF: C21H2206 (370)

The compounds shown in Table 9 were prepared analogously to the procedure of Example 65:

EXAMPLE 70 11-Hydroxy-4-methoxy-9-methyl-3- (1-O-tetrahydropyranyl-2-oxy) -3-methylbutyl) -7H-dibenzo [b, g] [1,5] dioxocin-5 -one

och3 0

100 mg (0.27 mmol) of penicillide (Ib) in 1 ml of absolute methylene chloride are stirred at 25 ° C for 12 hours with 72 μl (0.8 mmol) of dihydropyran and amounts catalysts of p-toluenesulphonic acid. After addition of 10 ml of methylene chloride, the mixture is washed with aqueous bicarbonate, washed until neutral, dried and evaporated. After chromatography of the residue on silica gel (Si 60) in petroleum ether / ether (2: 1), 65 mg (53/6 theory) of a colorless solid is obtained by fractional elution. MS: EI: 456, 372, 354, 312, 269. Molecular formula: C26 H32 O7 * 456)

EXAMPLE 71 4-Dimethoxy-4-methyl-S-d-hydroxyimino-S-methylbutyl-H-dibenzo [f], &lt; 5-dioxocin-5-one

4,11-di-methoxy-9-methyl-3- (1-oxo-3-methylbutyl) -7H-dibenzo [b] [1,5] dioxocin-5-one (100 mg, 0.26 mmol) is stirred was stirred at 25 ° C for 60 hours in 3 ml of glacial acetic acid, 36 mg (0.52 mmol) of hydroxylamine hydrochloride and 43 mg (0.52 mmol) of sodium acetate. After evaporation in a high vacuum the residue is dissolved in methylene chloride, the solution is washed with water and dried, and the evaporation residue is subjected to chromatography on silica gel (Si6G) in ether / petroleum ether (2: 1).

Yield: 40 mg (39% of theory) of a colorless solid. MS: EI: 399, 367, 325. SP! C22H25N06 1399 &gt; 59-

EXAMPLE 72 3- (i-Azido-3-methybutyl) -1-hydroxy-4-methoxy-9-methyl-7H-dibenzo [b] [3] oxadiazin-5-one

4.6 g (X7.6 mmol) of triphenylphosphine and 29.3 ml of a freshly prepared 0.6N solution of hydrazoic acid in toluene are added to 6 g (X6, X mmole) of penicillide (Ib) in 500 ml of tetrahydrofuran. To this mixture is added dropwise, 2.7 ml (X7.6 mmol) of diethyl azodicarboxylate, under an atmosphere of argon. The resulting mixture is stirred at 25 DEG C. for 12 hours. After dissolution with methylene chloride, the mixture is washed with aqueous bicarbonate; then dried and evaporated. Following silica gel chromatography (Si60) in diethyl ether / petroleum ether (2: 1), 5.6 g (88% of theory) of an inorganic solid is obtained. MS (ε): 397, 355, 299, X76, X63 SF: C21 H23 W3 O5:

EXAMPLE 73 3- (1-Azido-3-methylbutyl) -4,11-dikethoxy-9-methyl-7H-dibenzo [b] [7-a] dioxocin-5-one

The title compound was prepared analogously to the procedure of Example 72. MS (EI): 411, 369, 314, 383, 163; EXAMPLE 74 3- (1-Amino-3-methylbutyl) -1-hydroxy-4-methoxy-9-methyl-7H-dibenzo [b, g], 3,5dioxocin-5-one

63.3 ml of a solution of 20 g of boric acid and 20 g of nickel dichloride.and 1 H in 500 ml of ethanol are added to 5.63 g (14 mmol) of the compound of Example 72. To this mixture, 1.1 g (28.4 mmol) of sodium borohydride are added dropwise, dropwise, in 20 ml of ethanol. After stirring at 25 ° C for 12 hours the mixture is evaporated in vacuo, the residue is dissolved in methylene chloride and the solution is washed with water. After drying and evaporation, the residue is purified by silica gel chromatography (Si60) in methylene chloride / methanol / concentrated aqueous ammonia (200: 10: 1).

Yield: 3.8 g (76% of theory) of a colorless solid. MS (DCI): 372, 355 SF: C2-CH3 CN (371)

EXAMPLE 75 3- (1-amino-3-methylbutyryl) -4,11-dimethoxy-9-methyl-7H-dibenzo [b, g] [1,5] dioxocin-5-one

The compound was prepared analogously to the procedure of Example 74. MS (FAB): 386, 369, 355Â ° C. C22 H27 NO5 (385)

EXAMPLE 76 11- (4-Diethylaminobutyloxy) -3- (1-hydroxy-3-methylbutyl) -4-methoxy-9-methyl-7H-dibenzo [b] [1,5] dioxocin-5one

118 mg (0.23 mmol) of the compound of Example 10 are stirred at 70 ° C in an argon atmosphere for 12 hours with 1 ml of dimethylformamide, 48 μl (0.46 mmol) of diethylamine and catalytic amounts of sodium. After evaporation in a high vacuum the residue is dissolved in methylene chloride, and the solution is washed with water, dried and evaporated. After chromatography on silica gel (Si60) in concentrated methylene chloride / methanol / aqueous ammonia, there is obtained 86 mg (74% of theory) of a colorless solid. MS (DCI): 500, 484 SF: C₂HHNNNO ((499) -74-

EXAMPLE 77 3- (1-Hydroxy-3-methylbutyl) -4-methoxy-9-methyl-9-methyl-11-methylsulfonyloxy-7H-dibenzo [b, f] [1] dioxocin-5-one

A solution of 0.14 ml (1.0 mmol) of triethylamine and 85 μ (1.1 mmol) of methanesulfonyl chloride is added at 0 ° C under argon to 150 mg (0.4 mmol) of penicillin ( Ib) in 3 ml of methylene chloride, and the mixture is stirred at 25 ° C for 12 hours. After acidification to a pH of 2, extraction with methylene chloride, washing and drying and evaporation, the following is obtained on silica gel chromatography (Si60) in ether / petroleum ether (2: 1) 75 mg (41% of theory) of a colorless solid. MS (EI): 450, 393, 365, 347 SF: C22 H26 O8 S * 450)

EXAMPLE 78 4,11-Dimethoxy-3- (1-hydroxypropyl) -9-methyl-7H-dibenzo [b, f] [L, 57-dioxocin-5-one

0.7 mmol (1.4 mmol) of a 2M solution of ethylmagnesium bromide in tetrahydrofuran is added, under argon atmosphere, at 0 ° C, 53 mg (0.15 mmol) of the compound of Example 101, in 4 ml of absolute tetrahydrofuran, and the mixture is stirred at 25 ° C for 1 hour. After addition of 2 ml of 1N hydrochloric acid, the mixture is diluted with methylene chloride, washed with water, dried and evaporated.

After chromatographic purification on silica gel Si6 O (petroleum ether / ether gradient), 36 mg of the title product (62% of theory) were obtained as a colorless solid. MS (EI): 358, 329, 311, 299, 283, 242. SF: C25H32O8 * 358)

The compounds shown in Table 10 were prepared analogously to the procedure of Example 78.

Table 10 H3C0 Ο Ί H3CQ ^ <vvI / m. (EI) SF OH 386, 329, C22H266, 61131, 299, (386) 79 (CH3) 3 283, 242 OH 372, 329, C21H246, 61131, 299, (372) (CH 3) 2 283 OH 344, 283 C 19 H 20 O 6 1 (344) 81% CH 3 OH 356, C 20 H 20 O 6. (356) 82 - (CH 2) 5 - CH 3 OH 406, 325, C 24 H 226 6122 (406) Vi, OH 372, 329, C21H246, 61131, 299, (372) 85 '(CH2) 2-CH3 283,

Table 10 continued

Ex. R2 No.

Formula SF (EI) 386, 299, 242 311, 283, C22H266 (386) 412, 283329, C24H286 (412) 440, 167283, C24H21C106 (440.5) 384, 283, 329, 242, 6 (384) 424, 123, 135 109 C24H21 ° 6F (424) 448, 301, 242 399, 271, C27H28 ° 6 (448) 420, 269, 44402, 119, C25H24-5 (420) 402, 119 C25H24O6 (420) Η -78-

EXAMPLE 94 3- (1-Chloro-3-methylbutyl) -1-hydroxy-4-methoxy-5-methyl-7H-dibenzazepine-1,2,3-dioxocin-5-one 0

200 mg (0.54 mmol) of penicillide (Ib) are heated at reflux for 5 hours (in the presence of moisture) in 1 ml of dioxane and 0.38 ml (5.2 mmol) of thionyl. After evaporation in vacuo the residue is dissolved in methylene chloride, and the solution is washed with aqueous sodium bicarbonate and then with water, dried and evaporated.

After chromatography on silica gel Si60 (ether / petroleum ether (2: 1) 187 mg (93% of theory) of a colorless solid is obtained. EXAMPLE 95 3- (1-Chloro-3- methylbutyl) -4,11-dimethoxy-9-methyl-7H-dibenzo [b, g] [1,5] dioxocin-5-one

The title compound was prepared analogously to the procedure of Example 94. MS (EI): 406, 404, 313, 163 SF: C22H25C105 (404.4) EXAMPLE 96 4,11-Dimethoxy-9- (3-methylbutyl) -7H-dibenzo [h, g] [1,4] dioxocin-5-one

The title compound was prepared analogously to the procedure of Example 97. MS (EI): 370, 342, 325, 313, 299 SF: C22 H26 O5 * 37. EXAMPLE 97 11-Hydroxy-4-methoxy-9- 3- (3-methylf utyl) -7 H -benzazepi [b, g] [1,5] dioxocin-5-one

131 mg (0.3 mmol) of the compound of Example 94 in 2.5 ml of toluene and 200 ul (0.74 mmol) of tributyltin hydride are heated at reflux. After addition of 2,2'-azo-diisobutyronitrile (29 mg, 0.18 mmol), the mixture is heated at reflux for a further 2 hours, and is evaporated in vacuo and the residue is purified by chromatography on silica gel Si 60 using petroleum ether / ether (5: 1) as eluents.

Yield: 128 mg (90% of theory) of colorless crystals of diethyl ether. EXAMPLE 98 4,11-Dimethoxy-9-methyl-3- (3-methyl-1-butenyl) -7H-dibenzo [b, g] [1,5] dioxocin-5-one

HgCO O

(3.0 mmol) of the compound of Example 95 were dissolved in 10 ml of dimethylformamide, 2.2 ml (15.3 mmol) of 7-methyl-l, 5,7-triazabicyclo [2.2.1] 4.4.0] dec-5-ene and 0.65 g of copper (I) oxide are stirred at 80 ° C for 12 hours under an argon atmosphere. After filtration, the mixture is evaporated in vacuo, the residue is dissolved in methylene chloride, 1N aqueous hydrochloric acid is added, and then the mixture is washed with water, dried and evaporated. After chromatography on silica gel Si60, petroleum ether / ether (3: 1) yields 730 mg (65% of theory) of a glassy solid. MS (EI): 368, 353, 335, 323, 218, 203 SP: C22H25O5368:

EXAMPLE 99 4-Methoxy-9-methyl-3- (1-N - ((S) -2-pyrrolidon-5-carboxamido) -3- methylbutyl) -7H-dibenzo [b] [1,4] dioxocin-5-one

85 μΐ (0.49 mmol) of diisopropylethylamine in 1 ml of dimethylformamide is added at -55 ° C in an argon atmosphere to (S) -6- -2-pyrrolidone-5-carboxylic acid. After addition of 38 μl (0.54 mmol) of methanesulfonyl chloride, the mixture is stirred at -55 ° C for 30 minutes. Then, 166 pl (1.2 mmol) of triethylamine and 0.2 g (0.54 mmol) of the compound of example 74 are added dropwise in 1 ml of dimethylformamide. After stirring for 30 minutes at 25 ° C, the mixture is diluted with methylene chloride and washed at a pH of 3-4 with water, dried and evaporated. After chromatography on silica gel Si60 in methylene chloride / methanol (20: 1) 92 mg (33% of theory) of a colorless solid is obtained. MS (DCI): 483, 325, 220, 186 SF: C26 H30 N2 O7 (482) 34-

EXAMPLE 100 4,11-Dimethoxy-3- (1,2-epoxy-3-methylphthyl) -9-methyl-7H-dibenzo [g], 5,7-dioxocin-5-ene

43 mg (0.12 mmol) of the title compound

Example 98, in 2 ml of dichloromethane, are stirred at 25Â ° C for 3 hours with excess meta-chloroperbenzoic acid. After washing with aqueous bicarbonate, drying and evaporation, the residue is chromatographed on silica gel Si60 in petroleum ether / ether (1: 1). 12 mg (21% of theory) of a colorless solid is obtained in the main fraction. MS (EI): 384, 267, 239, 234, 219, 191 SP. C22H24O6 <384) -85-

EXAMPLE 101 4,11-Dimethoxy-9-methyl-3-oxophenyl-7H-dibenzo [h, q], S-dioxocin-5-one

A mixture of ozone / oxygen at -60Â ° C is added, to the saturation, in 5.6 g (15.2 mmol) of the compound of Example 98 in 100 ml of methylene chloride and 10 ml of methanol in an apparatus (Standard) / Orga-nikum, 9th edition, page 298 ff., VEB Deutscher Verlag der Wissenschaften. After the addition of 19 ml of tributylphosphine the mixture is warmed to 25 ° C with stirring, washed with hexane and chromatographed on silica gel Si60 in ether / petroleum ether (1: 1).

Yield: 2.0 g (40% of theory) of colorless crystals. MS (EI): 328, 300, 299, 283, 269 SF: c18H166 (328) 86-

EXAMPLE 102 3- (1,4-Dihydroxybutyl) -4,11-dimethoxy-9-methyl-7H-dibenzo [b, q] -A, dioxocin-5-one

The primary ozonols prepared from 100 mg (0.26 mmol) of the compound of Example 89 by the procedure of Example 101 are reduced by the addition of an excess of sodium borohydride. MS (EI): SF: C 21 H 24 7 (388)

EXAMPLE 103 3-Methyl-11-methoxy-7H-dibenzo [b, g] [1,5] dioxocin-5-one

O

(2-methoxy-6-chloromethyl) -5-methyl-oxybenzoic acid (100 mg, 0.32 mmol) in absolute dimethylformamide (2 ml) and 1,8- diaza-bicyclo [5.4.0] undec-7-ene are stirred at 80 ° C under argon for 12 h. After evaporation, in a high vacuum, residue 6 dissolved in methylene chloride, and the solution is washed with water, dried and evaporated. After chromatography on silica gel Si60 in methylene chloride, 17 mg (20% of theory) of a colorless solid is obtained. MS (EI): 270, 255, 241, 225 SF! EXAMPLE 104 11-Carboxymethyloxy-S- (X-furanyl) -3-methylbutyl) -4-methyl-L-9-methyl-7H-dibenzo [b] dioxocin-5-one

O

100 mg (0.2 mmol) of the compound of Example 11 is stirred at 25 ° C for 2 hours in 2 ml of formic acid. After evaporation, under high vacuum, 90 mg (96% of theory) of a colorless solid is obtained. 1 H-NMR (Î'ppm): 89-

EXAMPLE 105 3- (1-Hydroxy-3-methylbutyl) -4-methoxy-11- (2-hydroxyphenoxy-3-phenoxypropyloxy) -9-methyl-7H-dibenzo [l, 4-oxo-5-oxoocyn-5-one och3 HO 0

100 mg (0.23 mmol) of the compound of Example 24 is stirred at 25 ° C for 2.5 hours in 1% methanolic sulfuric acid. After dilution with methylene chloride, the obtained mixture is washed with water and aqueous bicarbonate. After drying, evaporation and chromatography on Si6 O-silica in diethyl ether, 22 mg (20% of theory) of a colorless solid is obtained. MS (EI): 460, 389 25 32 6 EXAMPLE 10β 11- (2,3-Dihydroxypropyloxy) -3- (1-hydroxy-3-methylbutyl) -4-methoxy-9-methyl -7B-dibenzo [b, c] [5,7] dioxocin-5-one

O

II 100 mg (0.23 mmol) of the compound of Example 24 is stirred at 25 ° C for 12 hours in 2 ml of tetrahydrofuran and 0.5 ml of 1% aqueous perchloric acid. After addition of methylene chloride, the mixture is washed with water and aqueous bicarbonate, is dried and evaporated. After chromatography on silica gel Si60 in methylene chloride / methanol (95: 5), 12 mg (11% of theory) of a colorless solid is obtained. MS (EI): 446, 389, 359, 353, 269, 179 SF! EXAMPLE 107 10-Bromo-11-hydroxy-3- (1-hydroxy-3-methylbutyl) -4-methoxy-9-methyl-7H-dibenzo [b, g] [1 1-hydroxy-3- (1-hydroxy-3-methylbutyl) -4-methoxy-9-methyl-7H-dibenzo [b] [1,4] oxazin-5-one (EXAMPLE 108) and 8- 3-oxo-5-one (EXAMPLE 107)

(Example 107) (Example 108) 1 g (2.7 mmol) of penicillin (Ib) is stirred at 90 DEG C. under argon with 0.8 g (5.7 mmol) of potassium carbonate and 2 ml (25 mmol) of bromo-nitromethane in 6 ml of dimethylformamide was stirred for 23 hours.

After evaporation in a high vacuum the residue is dissolved in 1N aqueous hydrochloric acid and extracted thoroughly with diethyl ether. After drying and evaporation the residue is separated into two fractions on silica gel Si 60 in methylene chloride / ethyl acetate (10: 1) which, after evaporation in vacuo, are separated on silica gel RP 8, in acetonitrile / water (68:32) and, in addition to the starting material, provide chromatographically uniform products. -92-

EXAMPLE 107

Yield: 457 mg (37% of theory) of a colorless solid MS (EI): 452, 450, 395, 393, 349, 347, 179 SF: C21H2306Br (451) EXAMPLE 108

Yield: 36 mg (2.9% of theory) of a colorless solid. MS (EI): 452, 450, 395, 393, 349, 347, 179 SF: C21H2306Br (451)

In addition, during the preparation of Examples 107 and 108 288 mg (20% of theory) of the compound (Example 107a) 8,10-dibromo-11-hydroxy-3- (1-hydroxy-3-methylbutyl) ) -4-methoxy-9-methyl-7H-dibenzo [b, g] [1,5] dioxocin-5-one / tetrahedron Letters 45, 3941, (1974)

EXAMPLE 109 4-Hydroxy-11-methoxy-9-methyl-3- (3-methyl-1-butanoyl) -7H-dibenzo-.alpha., 7,7dioxocin-5-one

10.8 ml of a 1M solution of boron tri-bromide in dichloromethane is added dropwise at -70 ° C in an argon atmosphere to a solution of 6.2 g (16.1 mmol) of 3- - (3-methyl-1-butanonyl) -4,11-dimethoxy-9-methyl-7H-dibenzo [b, g], 5,7-dioxocin-5-one in 160 ml of dichloromethane. After 1.5 hours, 6 ml of methanol is added and the solution is warmed to room temperature after a further 40 minutes. Wash with a solution of sodium hydrogen carbonate and water, dry over magnesium sulfate and concentrate in vacuo. The residue is purified on a silica gel column using petroleum ether / ethyl acetate (6: 1).

Yield: 4.0 g (67% of theory) MS (EI): M + + 370 SF: C 21 H 22 O 6

The compounds shown in Table 11 are prepared analogously to the procedure of Example 109:

Table 11

Ex.

OH O

(HEY )

SF 110

H 356, 299, 221, 137 C 20 H 20 O 6 (356) 111 -ch2-ch3 384, 165, 164, 149, 136 C22H246 (384) EXAMPLE 113 4-Hydroxy-3- (1-hydroxy-3-methylbutyl) -11-methoxy-9-methyl-7H-benzo [b] [5,7] dioxocin-5-one

OH OH

-95-

2.2 g (5.9 mmol) of the compound of example 109 are dissolved in 40 ml of tetrahydrofuran; then 7 ml of glacial acetic acid and 0.96 g (15 mmol) of sodium cyanoborohydride are added. After 14 hours at room temperature, the mixture is concentrated in vacuo, the residue is dissolved in dichloromethane and the solution is washed with sodium hydrogencarbonate and water, dried over magnesium sulfate and concentrated in vacuo. Purification is performed by column chromatography (silica gel) using dichloromethane / methanol (150: 1) as the eluent.

Yield: 1.3 g (39% of theory) MS (EI): M + = 372 sf: c 21h 24o 6

The compounds shown in the following tables 12 and 13 were prepared analogously to the procedure of Example 113:

Table 12

Table 12 continued

Ex. R12 Formula SF N2. (EI) 114 H 358, 301, 283, 165, 137 C20H226 (358) 115 -ch2-ch3 386, 368, 311, 165 C22H266 (386) 116 / ch3-ch2-ch 414, 357, 339 , 193 C 24 H 30 ° 6 (414) η 3

Table 13

432, 345, 277, 285, 329, 303, (432) 117 288

Table 13 below is the following: Formula (EI) SF 118 - "a 4461 311, 239 C28H30 (446) 119 -ch = ch2 382, 281, 175 C23H26 (382) 120 -ch2-ch3 384, 327-177, 151 EXAMPLE (R, S) -hydroxy-3-methylbutyl-4,7-dimethoxy-9-methyl-7H-dibenzo [b, g] [1,5] dioxocin-5-one

(3-methyl-1-butanoyl) -4,11-dimethoxy-9-methyl-7H-dibenzo [b, g] [5] dioxocin-5-one (158 g, 0.41 mmol) dissolved in 2 ml of tetrahydrofuran and 0.1 ml of water. 23 mg (0.61 mmol) of sodium borohydride are added, and the mixture is stirred overnight at room temperature. Excess sodium borohydride is destroyed by the addition of a few drops of acetic acid. The mixture is concentrated, in vacuo, the residue is dissolved in dichloromethane and the solution is washed with water. The organic phase is dried over magnesium sulfate, is concentrated and purified by silica gel column chromatography using petroleum ether / diethyl ether (1: 1).

Yield: 13% of theory. MS (EI): M + = 386. Example 122 4,11-Dimethoxy-3-hydroxymethyl-9-methyl-7H-dibenzo [b, g], 5,7dioxocin-5-one

The title compound was prepared analogously to the procedure of Example 121.

Yield: MS (EI): 330, 180, 150 SP: C18H1806 (330)

The compounds shown in the following table 14 are prepared analogously to the procedure of Example 121:

fix. Formula SF NS. (EI) 123 / ch3 -CHNCH2 414, 297, 315, 151 C24H306 (414) 124 -ch2-ch = ch2 412, 297, 355, 151 C24H286 (412) 297, 369, 285, C25 H30 O6 (426) 269 0 11 CHO 1 DC: 504 486, (m + nh4 + 469, c27H348 (486) 126 -ch2-co-C-CHO1H430, (428) 128 -ch2-ch3 400, 297, 343, 269 C23H286 (400) 129_CH2> 462, 297, 405, 269 C 28 H 30 ° 6 (462)

Table 14 continued

Ex. R12 NS.

Formula SF (EI)

J 130 -ch2-ch2-ch3 414, 297, 357, 151 C24H306 (414) 131 -ch2-ch2- <(). DCI: 494 (M + NH4 +) 476, 459, 419, 355 C29H32O6 (476) 132 -CH (C6H5) 2 FAB: 521, 167355, C34H34O6 (538) , 451, 506, 449, C25H21O6 (507) 297 134

486, 429, 371, 297, 269 C28H36O8 (486)

135 -CH

2 FAB: 515 (M + Na +), C29H32O7 CH3 492, 475, (492) 355, 154 136 137 -CH2-C-NH2 -CH2-CH2-Br 440, 315, C26H32 (297, 151 (440) 429, 412, C23H27372, 297353, (429) 480, 478, C23H27462, 343, 460, 297 (479)

EXAMPLE 139 3- (1-Hydroxy-3-methylbutyl) -4- (2,3-dihydroxypropoxy) -11-methoxy-9-methyl-7H-dibenzo [b], 7A, 5] dioxocin-5-one

OH

HO

HO 0 ^ O

100 mg (0.21 mmol) of the compound of Example 134 are dissolved in 5 mL of 80% acetic acid. After a reaction time of 5 hours at ambient temperature the solution is concentrated in vacuo and the residue is co-distilled (2x) with toluene and purified by column chromatography (silica gel), using dichloromethane / methanol (25: 1).

Yield: 53 mg (58% theory) MS (EI): 446, 239, 151 SP! C24 H30 O8 (446) -103-

EXAMPLE 140 3- (1-Hydroxy-1,3-dimethylbutyl) -4,11-dimethoxy-9-methyl-7H-dibenzo [b, g], 5,7dioxocin-5-one

The title compound was prepared according to the procedure described in Example 1, starting from the title compound as a white solid (100mg, 0.26mmol) of 4,11-di-methoxy-9-methyl-3- (3-methylbutan-1-onyl) -7H-dibenzo [b, g] -one are dissolved in 5 ml of absolute tetrahydrofuran in an argon atmosphere, whereupon 0.2 ml (0.6 mmol) of a 3M solution of methylmethyl bromide in diethyl ether is added at the temperature environment. After 4 hours, quench the reaction by adding 0.2 ml of an ammonium chloride solution. The mixture is concentrated, in vacuo, the residue is dissolved in dichloromethane and the solution is washed with water. After drying the organic phase over magnesium sulfate, the organic phase is concentrated, and the residue is purified by column chromatography (silica gel) using petroleum ether / ethyl acetate (10: 1).

Yield: 52 mg (50% of theory). MS (EI): 400, 343, 283 SF: C23H2806 (400) -104-

EXAMPLE 141 4-Chlorophenyl-3- (1-chlorophenyl-1-hydroxy-3-methylbutyl) -11-methoxy-9-methyl-7H-dibenzo [b, -one

Cl Cl

The title compound was prepared analogously to the procedure of Example 140.

Yield: 48% of theory. MS (EI): 578, 576, 519, 478, 363, SP: C33 H30 O12

The compounds pooled in the following tables 16 and 17 were prepared analogously to the procedure of Example 140. -

Table 16 Ο R1 Ο 1 II 1 II <ch3 Εχ. NS. (Formula) (EI) 5F 142 or 430, 329, 373, 223 C27H26O5 (430) 143 -CH2-? 444, 401 C28H285 (444) 144 -ch = ch2 380, 323, C23H24O5 (380) 145 -ch2-ch3 382, 325, 175, 339, 201, C23H26-5 (382)

Table 17

Ex. N2. (EI) 146 och 3 412, 311, 355, 283, 357, 147 408, 307, 351, 278, 323, C24H286 (412) C25H285 (408)

SF-107-

EXAMPLE 148 11-Ethoxy-4-methoxy-9-methyl-3- (3-methyl-1-methylenebutyl) -7H-benzo [b, g] dioxocin-5-one och 3

100 mg (0.25 mmol) of the compound of Example 66, dissolved in 4 ml of absolute tetrahydrofuran, are added dropwise in an argon atmosphere to a suspension of 150 mg (0.36 mmol) of methyl bromide and sodium amide (instant ilide). After a reaction period of 14 hours at ambient temperature, a little acetone is added, the solid constituents are separated and the solution is concentrated in vacuo. The residue is purified by column chromatography (silica gel) using petroleum ether / ethyl acetate (6: 1).

Yield: 28 mg (28% of theory). MS (EI): 396, 232, 190 SF: C24H2805 (396) -108-

EXAMPLE 149 11-Ethoxy-3- (1-hydroxymethyl-3-methylbutyl) -4-methoxy-9-methyl-7H-dibenzo [b, c] [1,5] dioxocin-5-one

2 ml (1 mmol) of a 0.5M solution of 9-borobicyclo [3.3.1] nonane in hexane are added dropwise under argon to a solution of 130 mg (0.33 mmol) of the compound of Example 148 was dissolved in 4 ml of absolute tetrahydrofuran. After 14 hours at room temperature, a few drops of ethanol, 2 ml of 2N sodium hydroxide solution and 0.5 ml of a 30% solution of hydrogen peroxide are added. The mixture is stirred vigorously for 3 hours and then concentrated carefully and the residue is dissolved in dichloromethane. The solution is washed with water, and the organic phase is dried over magnesium sulfate and concentrated, and the residue is purified by column chromatography (silica gel) using petroleum ether / ethyl acetate (6: 1 ).

Yield: 29 mg (20% of theory). EXAMPLE 150 11-Hydroxy-3- (1-hydroxy-3-methylbutyl) -4-methoxy-9-methyl-10- (4-methylbutyl) prop-2-enyl-7H-dibenzo [b, g] [1,5] dioxocin-5one

II 100 mg (0.25 mmol) of the compound of Example 20, dissolved in 2 ml of dimethylformamide, are heated to 160 ° C in an argon atmosphere for 14 hours. The solution is then concentrated, the residue is dissolved in dichloromethane and the solution is washed with water. After concentration of the dichloromethane phase, the residue is purified by column chromatography (silica gel) using petroleum ether / ethyl acetate (6: 1).

Yield: 14 mg (1456 theory). MS (EI): 412, 355, 325, 309 SF: C 24 H 28 O 6 110-

EXAMPLE 151 11-Hydroxy-3- (1-hydroxy-3-methylbutyl) -4-methoxy-9-methyl-10- (1-phenylprop-1-enyl) -7H-dibenzo [b, c] [1,5] dioxocin -5-one

The title compound was prepared from the compound of Example 25, proceeding analogously to the procedure of Example 150. MS (EI): 488, 431, 385, 150. C30B32O6 (448)

EXAMPLE 152 4-Chlorophenyl-3- (3-methyl-1-butanonyl) -11-Kethoxy-9-methyl-7H-dibenzo [b, c] [1,5] dioxocin-5one

Cl

The title compound was prepared from 4,11-dimethoxy-9-methyl-3- (3-methylbutan-1-onyl) -7H-dibenzo [b, g] [1,5] dioxocin-5 -one analogously to the procedure of Example 140. EXAMPLE 153 4-N-Chlorophenyl-3- (1-hydroxy-3-methylphenyl) -11-methoxy-9-methyl-7H-dibenzo [b, g] 1,5-dioxocin-5-one

Cl

The title compound was prepared from the compound of Example 152, analogously to the procedure of Example 121. MS (EI): 466, 409, 279, 363, 322 SF: C20H27C105 (466)

The compounds shown in Table 18 were prepared analogously to the procedure of Example 1: TABLE 18

Ex. R1 No. r15 r6 R® Formula SF (EI) 154

H OCH 3 372, 315 C 21 H 24 O 6 269, 243, 228 155 OH f

H ch3

H 356, 299 C21H2405 269, 253 (356) 227

Br och3 434, 389, 203 432 C21H21Br05 218 (433)

OH 157 CHâ,ƒCHâ,,Oâ,, 400, 343, 325, 297, 149 C23 H28 O6 (418)

114-

EXAMPLE 158 4,11-Dimethoxy-8,9-dimethyl-3- (1-hydroxy-3-methylbutyl) -7H-dibenzo [b, g] [5] dioxocin-5-one

3.3 mmol of zinc chloride (1M in diethyl ether) are added, under an inert gas atmosphere, to 3 moles of methyl magnesium bromide (3M in diethyl ether), the mixture is stirred at 25 ° C, for 10 minutes, a solution of 0.15 mmol of the compound of Example 39 in 3 mL of anhydrous tetrahydrofuran / 6 mL of dimethyl sulfoxide is added, whereupon 5 mg of bis- (tri-phenylphosphine chloride ) -palladium- (II), and the obtained mixture is stirred overnight at 50 ° C. It is hydrolysed using 0.05 ml of 5N hydrochloric acid and dissolved in water / ether, and the solution is washed 3 times with ether, and the organic phase is washed with water, dried over sodium sulfate and chromatography on a silica gel column (chloride / methanol (100: 1) and then on a RP 8 (acetonitrile / water, 5: 6) column.

Yield: 10.1 mg of an oil (16.356 theory). EXAMPLE 159 4,11-Dimethoxy-3- (1-hydroxy-3-methylbutyl) -8,9,10-trimethyl-7H-imidazol-4-yl- dibenzo [b, c] [1,5] dioxocin-5-one

The title compound is obtained from the compound of Example 41, proceeding analogously to the procedure of Example 158.

Yield: 65% of theory. MS (EI): 414, 357, 339, 311, 270, 179 SF! C24 H30 O6 (414)

EXAMPLE 160 10-Bromo-11-methoxy-3- (1-hydroxy-3-methylbutyl) -4-ethenyl-9-methyl-7H-dibenzo [b, c] [1,5] oxazocin-5-one

The title compound is obtained from the compound of Example 39, analogously to the procedures adopted in Examples 65, 78 and 121. MS (EI): 462, 460, 405, 381, 359 SF: C 23 H 25 O 6 (461)

EXAMPLE 161 8-Bromo-4,11-dimethoxy-3- (1-hydroxy-1-ethenyl-3-methylbutyl) -9-methyl-7H-dibenzo [b, [1,4] dioxin-5-one

The title compound was prepared from the compound of Example 39, analogously to the procedure of Example 65, and then from Example 78. MS (EI): 492, 490, 435, 433, 363, 361, C24 H27 BrO6 (491) -118-

EXAMPLE 162 8-Ethenyl-11-hydroxy-3- (1-hydroxy-3-methylbutyl) -4-methoxy-9-methyl-7H-dibenzo [b, c] [1,4] dioxocin-5-one

och3 OH O

170 mg (0.38 mmol) of the compound of Example 108 in 7 ml of toluene are heated at reflux for 22 hours in an inert gas atmosphere with 18 mg (0.015 mmol) of tetrakis (triphenylphosphine) - palladium and 0.2 ml (0.75 mmol) of tributylvinyltin. The suspension is adsorbed onto the silica gel and eluted in fractions using petroleum ether / ether (2: 1). MS (EI): 398, 341, 323 Sf: C23H2606 (398)

The compounds shown in Table 19 were prepared analogously to the procedure of Example 162:

119- "SB

tx, W

COO-CMX

VO (M cn X sO 'w' CM U 440)

120

<3 νΟ sO Ό -ο «Ο Ο« Ο ~ Ο ~ ο ~ Ο - Ο ~ Osú OsO OCO οοο ΟνΟ CO? COOO moo mm mvo moo 00 οο X V X Ό * X X X <a < (ΙΟ ΙΟ ΙΟ ΙΟ ΙΟ ΙΟ ΙΟ ΙΟ ΙΟ ΙΟ '' 'ΙΟ ΙΟ ΙΟ ΙΟ ΙΟ ΙΟ ΙΟ ΙΟ ΙΟ ΙΟ ΙΟ ΙΟ ΙΟ ΙΟ ΙΟ ΙΟ ΙΟ ΙΟ ΙΟ ΙΟ ΙΟ Ό1 mmmmmm ** ** • s · »σ '* -lm co HN or io Ό CO in Ό Η mmmmmm Μ · * * 1 -' N. σ '' -1 IO θ 'IO Π3 γΗ θ' vO CO oo 'Ό Ό Ό Ό Ί Ί Ί Ί Ί Ί Ί Ί Ί Ί Ί Ί Ί Ί Ό Ό Ό Ό Ό Ό Ό Ό Ό Ό Ό Ό Ό Ό Ό Ό Ό Ό Ό Ό Ό Ό Ό Ό α *

I (Μ X U X X II X X X η χυ π X Π

Xm Xυ

ΟΟ Xυ m Xο (Μ X ϋ ιι Xυ

00 X Ο ιι X U

X

IO V v ω θ 'o Ό Ό sO Ό Ό N «Η 1H iH -121-

The compounds shown in Table 20 were prepared analogously to the procedure of Example 70:

CH3, CH3. No. R1 R5 Formula (EI) SF 0 11 171 &gt; &quot; (484) 311-1719. H 496, 412, C29H36O7 329, 299 t (496) 283 122-

EXAMPLE 173 4,11-Dimethoxy-3- (1-hydroxy-3-methylbutyl) -8-oxomethylene-9-methyl-7H-dibenzo [b, g] [1,2] dioxocin-5-one

The title compound was prepared from Example 162, analogously to the procedure of Example 101. MS (EI): 414, 385, 357, 327, 311. C23 H26 O7 14141 123-

EXAMPLE 174 8-Azidomethylen-4,11-dimethoxy-3- (1-hydroxy-3-methylbutyl) -9-methyl-7H-dibenzo [b, g] [1,5] dioxocin-5-one

The title compound was prepared from the compound of Example 173, analogously to the procedure of Example 72, by introducing (coupling) and subsequent separation of a silyl protecting group according to customary methods (see J. Amer. Chem. Soc. 94, 6190 (1972)). MS (EI): 441, 384, 341, 161, 28 Sp: C 23 H 27 N 306 (441)

EXAMPLE 175 4-Aminomethylen-4,11-dimethoxy-3- (1-hydroxy-3-methylbutyl) -9-methyl-7H-dibenzo [b, c] [1,5] dioxocin-5one

The compound was prepared from the compound of Example 174, analogously to the procedure of Example 74, by introducing (coupling) and removing a silyl protecting group according to customary methods (see J. Amer. Chem. Soc. 94, 6190 (1972)). MS (DCI): 416, 398, 384, 176, 162 SF: C 23 H 29 NO 6 (415)

The compounds shown in Table 21 were prepared from the compound of Example 173, analogously to the procedure of Example 78,

Ex. R Formula (EI)

SF

OH 176 430,373,355, 337,325 C27H30O7 (430) 177 CH3

522, 504, 486, 303, 345, 455, 269, 522,

OH

568,550,506, 315 C35 H36 O7 (568)

Diastereomer I Diastereomer II

126-

Table 21 (Continued)

Ex.

R Formula (EI)

SF 179

OH

470,452,415 C27H34O7 395,377 (470)

OH 180 458

Diastereomer I Diastereomer II C26H24 ° 7 (458) 181 182

492,474,435 C29H32O7 417,389 (492) 498,480,441, C29H38O7 415,397 (498)

OH 472,454,415,397, 379

Diastereomer I 472,454,415,379 Diastereomer II C27H36 ° 7 (472) 183

EXAMPLE 184 4,11-Dimethyl-3- (1-hydroxy-3-methoxybutyl) -8-hydroxymethylen-9-methyl-7H-dibenzo [b, f] [1,4] dioxocin-5-one

The title compound was prepared from the compound of Example 173, analogously to the procedure of Example 121. MS (EI): 416, 359, 341, 311, 297, 318, 233,

EXAMPLE 185 4,11-Dimethoxy-3- (1-hydroxy-3-methylbutyl) -8- (2-ethoxycarbonylethenyl) -9-methyl-7H-dibenzo [b, f] [1,5] dioxocin- ona och3

100 mg (0.24 mmol) of the compound of Example 173 are stirred in an inert gas atmosphere with ethoxycarbonylmethylenetriphenylphosphorane (168 mg, 0.48 mmol) in toluene (3 mL) at 80 ° C for 14 hours. After the addition of methylene chloride, the mixture is washed with 0.1N aqueous hydrochloric acid, is dried and evaporated. After chromatography on silica gel in methylene chloride containing 5% methanol, 103 mg (88% of theory) of a colorless solid is obtained. EXAMPLE 186 4,11-Dimethoxy-3- (2-ethoxycarbonylethenyl) -9-methyl-7H-dibenzo [b] dioxocin hydrochloride -5-one

The title compound was prepared from the compound of Example 101, analogously to the procedure of Example 185. MS (EI): 398, 353, 248 SF: C 22 H 207 (398)

EXAMPLE 187 11-Hydroxy-3- (1-hydroxy-3-methylbutyl) -4-methoxy-9-methyl-8-nitro-7H-dibenzo [b, g] [5] dioxocin-5-one

150 mg (0.4 mol) of penicillide are dissolved in 15 ml of methylene chloride and the solution is stirred for 1 hour under an inert gas at a bath temperature of -68Â ° C, after addition of 0.8 ml of a 0.5M solution of nitronium tetrafluoroborate. The reaction mixture is poured onto ice. After extraction with methylene chloride, washing with water and bicarbonate, drying and evaporation, the residue is chromatographed on silica gel in petroleum ether / ether (1: 1). After evaporation, 86 mg (51% of theory) of a yellowish solid is obtained. MS (EI): 417, 399, 360, 342 SF: C 21 H 23 NO 4 (417)

EXAMPLE 188 18-Bromo-11-hydroxy-3- (1-hydroxy-3-methylbutyl) -4-methoxy-9-methyl-8-nitro-7H-dibenzo [b, g] [1,7] dioxin-5-one

The title compound was prepared from the compound of Example 107, analogously to the method of Example 187. MS (EI): 497, 495, 479, 477, 440, 438 SP: C21 H22 NO8 (496) EXAMPLES 189/190 8-Chloro hydroxy-3- (1-hydroxy-3-methylbutyl) -4-methoxy-9-methyl-7H-dibenzo [e] [1,4] dioxocin-5-one

8,10-Dichloro-11-hydroxy-3- (1-hydroxy-3-methylbutyl) -4-methoxy-9-methyl-7H-dibenzo [b, g], l, dioxocin-5-one

100 mg (0.27 mmol) of penicillide was 2 ml of ethanol / water (1: 1), stirred at 20 ° C for 12 hours, after addition of 36 mg (0.27 mmol) of N-chlorosucci- Nimide and 70 mg (0.26 mmol) of iron (II) chloride (6H20). After extraction with methylene chloride, washing with water and drying, the mixture is chromatographed in fractions on silica gel in petroleum ether / ether (1: 2). Two chromatographically pure products are obtained.

Example 189: Yield of 39 mg (= 35% of theory) of a colorless solid. MS (EI): 406, 349, 303 SF: C21H23C106 (406)

Example 190: Yield of 50 mg (42% of theory) of a colorless solid. EXAMPLE 191 10-Iodo-11-hydroxy-3- (1-hydroxy-3-methylbutyl) -4-methoxy-4-methyl- 9-methyl-7H-dibenzo [b, g] [1,5] dioxocin-5-one

The title compound was prepared analogously to the procedure of Examples 189 and 190 using iodonium chloride as the halogenating reagent. EXAMPLE 192 4,11-Dimethoxy-3- (1-hydroxy-3-methylbutyl) -8-iodo-9-methyl-7H-benzoyl chloride (498) / b, g7 / 1/57-dioxocin-5-one-13β-

For the preparation of the title compound, penicillide is reacted analogously to the procedure of Example 9 to form the monomethyl ether, and then the reaction proceeds analogously to the procedure of Example 191. MS (EI): 512, 455 , 427, 409, 368, (C22H23I06) (512)

The compounds pooled in Table 22 were prepared analogously to the procedure of Example 9:

Table 22

Ex. NS. (451) 195 H no2 431 * 374 C22H25N08 (431) 196 J H 512.455 * 409 C 22 H 25 J06 (512)

The compounds shown in Table 23 were prepared analogously to the procedure of Example 78

Ex. Formula SF No. (EI) 197 198 199

448,399,301 271,242 G27H28 ° 6 (448) 420,402,387, 361,328 C25H24 ° 6 (420) 458,420,402, 387,371 C25H24 ° 6 (420)

-138

Ex. R2 Formula SF NS. (HEY)

OH

398,329,311, 299,283 436,418,403, 285,135 436,418,403, 285,135 C23H266 (398) C25H247 (436) C25H247 (436)

Εχ. Ν3.

Formula (EI)

SF 204

436, 438, 403, 327, 297 C25 H34 O7 (436) OCH. 205

OH

482,464,449, 359,331 C30H266 (482) 206

498,480,465, 347,283 C30 H28 O7 (500)

412,339.31, 299,283 C24 H28 O6 (412) 207 140-

It should be emphasized that the present specification and the Practical Examples are intended only to illustrate - but not limit - the inventive scope of the present in effect, those skilled in the art will readily appreciate that the present invention allows obtaining other forms of execution also , provided they do not depart from the scope and spirit of the present invention. EXAMPLE 208 4,11-Dimethoxy-1-hydroxy-9-methyl-8- (1-tetrahydropyranyl-2-oxy) -oxymethylene) -7H-dibenzo [b, g] [1,5] dioxocin-5-one

The title compound was prepared from the compound of Example 184 by coupling and removal of a silyl protecting group according to customary methods (J. Amer. Chem. Soc., 9, 6190 (1972)) in analogy to Example 70. MS (EI): 500, 399, 341 SF: C28H360g (500)

EXAMPLE 209 3- (1-Amino-3-methylbutyl) -8-bromo-4,11-dimethoxy-9-methyl-7H-dibenzoylbenzaldehyde A dioxocin-

The title compound was prepared analogously to the procedures of Examples 72 and 74. MS (DCI): 464, 462, 462 (Μ + H), 449, 447, 408, 406 SF: C 22 H 26 BrNO 5 (464)

EXAMPLE 210 4,11-Dimethoxy-1-hydroxy-N-methyl-8- (1-pyrrolomethylene) -7H-dibenzo [b, g] oxadiazin-5-one

The title compound was prepared from the compound of Example 174 by treatment with equimolar amounts of 2,5-diethoxytetrahydrofuran and sodium acetate in acetic acid for 15 minutes at 100 ° C, work up by standard procedures of extracting chromatography. MS (FAB): 472 (M ++ Li) SF: C27 H31 N06 (465) EXAMPLE 211 3- (Methylsulfonylamido-3-methylbutyl) -3-bromo-4,11-dimethoxy-9-methyl-7H-dibenzo [b, 1 H -Docynocin-5-one

The title compound was prepared from the compound of Example 209, analogously to the procedure of Example 77. MS (DCI): 561, 559 (M + + NH4 +), 484, 486, 449, 447 SP: C 23 H 28 BrNO 7 (542 )

The compounds shown in Table 24 were prepared analogously to the procedure of Example 101: Table 24: Εχ. Ν °.

SF 212 213 -CO-OC2H5 458,401,355 C25H300 472,458,443 C26H320 429,415,401 oc2h5 214 42,385,467 C25H300 CH- 504,429,251 C3qH320g (458) g (472) 7 · (442) 7 (507) C 615 215 EXAMPLE 216 11-Hydroxy-3- (3-pyridyl) -7H-dibenzo [b, f] dioxocin-5-one-methoxyethane

32.6 mg (0.07 mmol) of the compound of Example 224 were stirred with 3 ml of iodomethane until the extract was completely consumed (TLC). Evaporation of excess iodomethane gave 41 mg (96.5% of theory) of the title compound. SP: C 28 H 32 JNO 6 (605) MS (FAB) 478, 307, 242, 154

The compounds shown in Table 25 were prepared analogously to the procedure of Example 162:

OCH

The compounds shown in Table 26 were prepared by alkylation of the compound of Example 184, according to processes already disclosed (eg, A.F.

Kluge et. al., J. Am. Chem. Soc., 9, 7827 (1972)), and by proven methods for the introduction and removal of silyl protecting groups. (E. J. Corey et al., J. Am. Chem. Soc., 94, 6190 (1972).

Table 26 och3

Ex. R SF MS (EI) NQ. (CH2) 20CH3 28H38 ° 9 (518) 518,500,398, 369,341,311 236 -CHg C24H308 (430) 430,373,341,311 237 (CH3) -CH3 -C26 H347 (458) 458,341,311 238 -CH2- ( (536) 536,415,163 239 / CH3 CHO-CH3 CH3 C27H36O7 (472) 472,415,341,311 150- m

%

The compounds shown in Table 27 were prepared analogously to the procedure of Example 162:

240 241 242 243 244 245 246

426.369.323, 282 C 25 H 30 ° 6 (426) 412,355.309, 268 C24H28 ° 6 (412) 448,391,345, 329,320 C27H28 ° 6 (448) 462,405,359, 318 C28H30 ° 6 (462) 454,351,310 C25H26 ° 6 · (454) 454,351,315, 269 C25H26 ° 6 ; (454) C26 H27 N0 (449) 474,377,365 C29 H30 O6 (474) 247

-151-

Ex. R MS (EI) SF NQ.

438, 355, 315, 254, 269, 269 (438)

455, 315, 269, C24 H25 N06 S (455)

C 22 H 26 N 6 O 398, 341.295, 233, 266, 254 (398)

The compounds shown in Table 28 were prepared from the compound of Example 251, analogously to the procedure of Example 78.

Table 28:

Ex. R MS (EI) SF No. 252 -CH, 416, 359,313, 272 C 23 H 28 O 7 (416)

Cl 512,455,409 253 C28H29C107 (512.5) C28H30 ° 7 478,421,375 254

EXAMPLE 255 9-Formyl-3- (1-hydroxy-3-methylbutyl) -4,11-dimethoxy-7H-dibenzo-Zb, 1,3-dioxocin-5-one

The title compound was prepared from the compound of Example 251, analogously to the procedure of Example 101. MS (EI): 400, 382, 343, 297 SF: C22 H24 O7 (400)

EXAMPLE 256 9- (2-Ester carboxyethylethenyl) -3- (1-hydroxy-3-methylbutyl) -4,11-dimethoxy-7H-dibenzo [b, g] A] dioxocin-5-one

The title compound was prepared from the compound of Example 255, analogously to the procedure of Example 185. MS (EI): 470, 452, 413, 383, 367. (470) EXAMPLE 257 9-Hydroxymethyl-3- (1-hydroxy-3-methylbutyl) -4,11-dimethoxy-7H-dibenzo [b, g], 5,7dioxocin-5-one

The title compound was prepared from the compound of Example 251, analogously to the procedure of Example 121 MS (EI): 402, 345.299, 258 SFI C 22 H 26 O 7 (402)

EXAMPLE 258 9-Bromo-3- (1-hydroxy-3-methylbutyl) -4,11-dimethoxy-7H-dibenzo [b] [c] dioxocin-5-one

The title compound was prepared analogously to the procedure of Example 1. MS (EI): 452 (M + +), 450, 395, 393, 349, 347 SF: C21 H23 BrO6 (451)

Claims (2)

Anspruch [en] A process for the preparation of compounds of general formula (I): In which R 1 and R 2 are identical or different and in each case - represent hydrogen, or - represent straight or branched alkyl, alkylthio, alkenyl or alkynyl containing in each case a maximum number of 12 atoms which are optionally substituted by halogen, azido, imino substituted by hydroxy, hydroxyl, cyano, cycloalkyl containing 3 to 8 carbon atoms, or by a trigonal and heptagonal saturated or unsaturated haterocyclic radical containing up to 4 hetero - atoms of the group consisting of nitrogen, sulfur and oxygen, or by aryl or aryloxy containing 6 to 10 carbon atoms, which in turn may be mono-substituted and tri-substituted by identical or different sub- of the group consisting of halogen, nitro, phenyl, phenoxy, cyano, straight-chain or branched alkyl, alkoxy or alkoxycarbonyl, each containing a maximum of 8 carbon atoms, or by a radic al of formula i or a group of the formula -NR1 R2, -COR or -OR, wherein R3 and R4 are identical or different and in each case signify hydrogen, or straight or branched chain alkoxy containing up to 10 carbon atoms, or aryl containing 6 to 10 carbon atoms or a group of the formula -S (O) p R13, R3, signifies hydrogen, hydroxyl, a linear or branched chain containing up to 10 carbon atoms, phenoxy, aryl containing 6 to 10 carbon atoms or the group wherein R and R are as defined above, R 3 represents hydrogen, cycloalkyl containing 3 to 8 carbon atoms, formyl, acyl containing up to 8 carbon atoms, tetrahydropyranyl, trifluoromethoxy or a group of the formula - (O) R 2, where p denotes an integer of 13 P 1 to 2, R represents straight or branched chain alkyl containing up to 8 atoms carbon atoms or the group wherein R and R have the abovementioned meaning, or R 2 represents straight or branched chain alkyl or alkenyl containing up to 10 carbon atoms, which is optionally substituted by hydroxy, halogen, cycloalkyl containing 3 to 8 carbon atoms, alkoxy or alkoxycarbonyl containing up to 8 carbon atoms, or by aryl containing 6 to 10 carbon atoms, which in turn may be substituted by halogen, hydroxy, alkyl, alkoxy- or alkoxycarbonyl group containing in each case up to 8 carbon atoms, or nitro or cyano, or by a saturated or unsaturated 3 to 7 ring heterocyclic radical containing up to 4 chosen hetero atoms of the group consisting of sulfur, oxygen and nitrogen, or by a group of the formula -NRâ, ... Râ, ... Râ, ..., I 1 H or is aryl having 6 to 10 carbon atoms, which is optionally substituted by halogen, hydroxy, nitro or cyano, or is identical or different and in each case - represents halogen, cyano, hydroxy or nitro - represent a heterocyclic radical having 3 to 7 ring atoms containing a maximum number of 4-hetero atoms selected from the group consisting of sulfur, oxygen and nitrogen or pyridyl-3-methoxy, or - represent aryl containing 6 to 10 carbon atoms, which in turn may be substituted by halogen, cyano, phenyl, nitro, straight or branched chain alkyl or alkoxy, each containing at most 8 carbon atoms, or hydroxyl, or - represent cycloalkenyl containing 3 to 8 carbon atoms, represent a group of the formula -NR1 R2, -COR or -OR9, wherein R1 to R2 have the abovementioned meanings, or R1 and R 2, R 2 and R 3, R 3 and R 4, R 5 and R 6, R 6 and R 7, or R 7 and S 8, in each case, together form a saturated or unsaturated pentane-to-hepatic carbocyclic radical optionally substituted by nitro, cyano, hydroxy, straight-chain or branched alkyl having up to 8 carbon atoms or a group of the formula -NR1 R2, -COR, or -OR, in which R are each independently hydrogen or straight or branched chain alkyl having up to 10 carbon atoms, which is optionally substituted by halogen, , nitro, cyano, hydroxy, or a group of the formula -NR1 R2, -COR or -OR9, wherein R1 to R3 have the above meanings, - represent aryl containing 6 to 10 carbon atoms, optionally substituted by nitro, cyano, halogen, alkyl, alkoxy or alkoxycarbonyl containing up to 8 carbon atoms or by a group of formula - Wherein R and R have the abovementioned meanings, or R 3 and R 4 together form a saturated or unsaturated pentane-to-hepatic carbocyclic radical and the physiologically acceptable salts thereof, characterized in that [ Compounds of general formula (II) R 1 R 2 R (II) in which R1 and R2 are as defined above, X1 is fluoro, chloro, bromo or iodo, and Y2 represents (C1 -C6) -alkoxy or aryloxy having 6 to 10 carbon atoms , are condensed to compounds of general formula (III) (III) wherein R 5 to R 6, R 14 and R 24 have the abovementioned meanings, and Z represents a typical hydroxy protecting group, such as for example tetrahydropyranyl, or compounds of formula (IIa) -162 - (IIIa) in which R 1, R 2 and Y have the abovementioned meaning, are condensed to compounds of general formula (IIIa) in which R 1, R 2, R 3, R 4, wherein &quot; 5-8 &quot; (IV) (IV): wherein R 1, R 2, R 3 and R 4 have the meanings given above, in inert solvents and with the elimination of hydrohalic acids, such as, for example, hydrogen bromide, R1 in which R 1 to R 8, R 14, R 15, Y and Z have the abovementioned meanings and then the hydroxy group is unblocked by the usual methods and the compounds are cyclized with water elimination, whereby the substituents R 1 to R 8 can be introduced (III), (III) and (IIIa), both before condensation, and after cyclization of the compounds of formula (IV), by means of known methods , such as, for example, alkylation, acylation, substitution, addition, elimination, rearrangement, oxidation, reaction with radicals or reduction, and if appropriate, then converting them to other functional groups, or characterized by [B] starting from natural substance of formula (Ii>) (Ib) (hereinafter referred to as '' penicillide '') -164- wherein R 1 is methoxy, 2 'R 2 is OH R 2 is methyl and R 2 is hydroxy, the substituents R 1, R 2 and R 3 are introduced by the usual methods mentioned in the process and are given hereinafter by way of example, such as, for example, rearrangement , alkylation, acylation, addition, elimination, oxidation, reaction with radicals or reduction in inert solvents, if appropriate, in the presence of auxiliary agents, such as, for example, active bases, acids, catalysts or reagents, and converting these substituents, as well as the substituents R1, R2, R3 and R4, on other functional groups. 2â. A process according to claim 1, wherein the compounds of general formula (I) and physiologically acceptable salts thereof are prepared in which R¹ to R² are identical or different and in each case represent hydrogen or - represent straight or branched chain alkyl, alkylthio, alkenyl or alkynyl containing in each case up to 10 carbon atoms which are optionally monosubstituted or tetra-substituted by identical or different radicals selected from the group formed by fluorine, chlorine, bromine, imido, imino, imino substituted by hydroxy, hydroxyl, cyano, cyclopropyl, cyclopentyl, cyclohexyl, or by pyrrolo, cyano, cyclopropyl, cyclopentyl, cyclohexyl, or by pyrryl, morpholino , piperidyl, oxiranyl or by phenyl which in turn may be mono-substituted with tri-substituted by identical or different substituents selected from the group consisting of fluoro, chloro, bromo, iodo, nitro, phenyl alkoxy or alkoxycarbonyl, each containing up to 6 carbon atoms, or a radical of the formula -Hi 9 10 11 or substituted by a group of the formula -NR1 R2, -COR2 or -OR, wherein R6 and R6 are identical or different and in each case signify hydrogen, straight or branched chain alkyl containing up to 8 carbon atoms, or phenyl, or a group of the formula -S (O) R 11 represents hydrogen, hydroxy, straight or branched chain alkyl or alkoxy containing up to 8 carbon atoms, phenoxy, phenyl or the group -NR , R 9 ??? is hydrogen, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohaptyl, formyl, acyl containing up to 6 carbon atoms, tetrahydropyranyl, trifluoromethoxy or a group of the formula -SO 2 R 5, wherein p is is an integer from 1 to 2, R is straight-chain or branched alkyl containing -166-  € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒwherein R1 and R2 are as defined above, or R12 represents straight or branched chain alkyl or alkenyl having a maximum number of Which is optionally monosubstituted to tetra-substituted by identical or different radicals selected from the group consisting of hydroxy, fluoro, chloro, bromo, cyclopropyl, cyclopentyl, cyclohexyl, alkoxy or alkoxycarbonyl group containing up to 6 carbon atoms, or phenyl, which in turn may be substituted by fluorine, chlorine, bromine, hydroxy, alkyl, alkoxy or alkoxycarbonyl, each containing at most 6 carbon atom, nitro or cyano, or is substituted by oxiranyl, pyrimidyl, pyridyl or by a group of the formula -NR1 R2, -COR or -OR, wherein R1 and R2 have the abovementioned meanings , or is substituted by a radical of formula or are each identical or different and in each case represent fluoro, chloro, bromo, iodo, cyano, hydroxy, nitro or pyridyl 3-methoxy, pyridyl, furyl, thienyl, 2,3-dihydrofuryl , dihydropyranyl or thiazolyl, oxiranyl or phenyl which are optionally substituted by fluorine, chlorine, bromine, phenyl, straight or branched chain alkyl or alkoxy containing up to 6 carbon atoms, or hydroxy, or - represent cyclobutenyl , cyclopentenyl or cyclohexenyl, represent a group of the formula -NR1 R2, -COR or -OR9 wherein R2 to R3 have the abovementioned meanings, or R1 and R2; R 2 and R 3 and R 4 together represent phenyl, cyclopentyl or cyclohexyl and R 2 and R 3 are identical or different and in each case, - represent hydrogen, or straight chain or branched alkyl having up to 8 carbon atoms, which is optionally substituted by fluorine, chlorine, bromine, cyano, hydroxy, or by a group of the formula -NR1 R2, -COR or -OR, wherein R 1 and R 2 have the abovementioned meanings, or represent phenyl, optionally substituted by nitro, cyano, fluoro, chloro, bromo, alkyl, alkoxy or alkoxycarbonyl containing up to 6 carbon atoms, po of the formula -NRR, where R and R are as defined above. 35. A process according to claim 1, wherein compounds of general formula (I) or physiologically acceptable salts thereof are prepared in which R¹ to R² are identical or different and in each case represent hydrogen, or - represent straight-chain or branched alkyl, alkylthio, alkenyl or alkynyl containing in each case up to 8 carbon atoms which are optionally monosubstituted or tetra-substituted by identical or different radicals selected from the group consisting of fluorine, chlorine, bromine, iodine, azido, imino, imino, imino substituted by hydroxy, hydroxyl, cyclopropyl, cyclopentyl, cyclohexyl, or substituted by morpholino, piperidyl, pyrryl, oxiranyl or phenyl, which in turn may be mono-substituted or tri-substituted by identical or different substituents selected from the group consisting of fluoro, chloro, phenyl, phenoxy or by straight or branched chain alkyl or alkoxy, a maximum number of 4 carbon atoms,. or are substituted by a radical of formula Or by a group of the formula -NR R f -COR or -OR, wherein R 1 and R 2 are identical or different and in each case - represent hydrogen, straight or branched chain alkyl containing a maximum number of Or a group of the formula -S (O) -R 11, R 11 represents hydrogen, hydroxy, trifluoromethyl, straight or branched chain alkyl or alkoxy having up to 6 carbon atoms, phenoxy, phenyl or the group -NR 9 R 10, R 9 and R 9 are as defined above, R 12 represents hydrogen, cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, formyl, acyl group having a maximum number of 4 carbon atoms, tetrahydropyranyl, trifluoromethyl or a group of the formula -S (O) pR, wherein p represents an integer from 1 to 2.13 R represents straight chain alkyl or branched, containing up to 4 carbon atoms, or represents alkyl or alkenyl of which is optionally monosubstituted and trisubstituted by identical or different radicals selected from the group consisting of hydroxy, fluoro, chloro, bromo, cyclopropyl, cyclopentyl, , cyclohexyl, alkoxy or alkoxycarbonyl containing up to 4 carbon atoms or by phenyl, which in turn may be substituted by fluorine, chlorine, hydroxy, or alkoxy containing up to 4 carbon atoms , or is substituted by oxiranyl or by a group of the formula -NR1 R2, -COR or -QR, wherein R1 to R2 are as defined above, or is substituted by a radical of formula or a pharmaceutically acceptable salt thereof. h II o or R 1a are the same or different and in each case are - fluoro, chloro, bromo, iodo, hydroxy or nitro, pyridyl-3-methoxy, or represent furyl, pyridyl, 2,3-dihydrofuryl, thienyl, dihydropyranyl, thiazolyl, phenyl or oxiranyl, which in turn may be substituted by fluorine, chlorine, methyl, isopropyl, phenyl or ethoxy, - represent a group of the formula -NR1 R2, -COR or -OR, in 12, which R and R have the abovementioned meanings, R and R are identical or different and represent hydrogen, straight or branched chain alkyl containing up to 6 carbon atoms, or phenyl. 4ã. 2. A process as claimed in claim 1, wherein the compounds of general formula (I) or physiologically acceptable salts thereof, η 8 14 15 κ to R, Rx and κ have the meanings given in claim 1, wherein 8, a) R can not represent hydroxyl, methoxy or acetyl, if R is methoxy, R , R 2, R 3, R 4, R 5 and R 6 are each hydrogen, R 2 is methyl and R 2 is B) R 3 and R 4 may not represent bromine and R 2 may not be hydrogen. . R 2 represents methoxy, R 1, R 2, R 3 and R 2 are hydrogen, R 2 is methyl and R 2 is OH OR -171- (C) R4 may not represent methoxy, if R3 is methoxy, R1, R2, R3, R4 and R7 are hydrogen, R6 is methyl and R7 is group O or methoxy, if R 1 to R 2 is the group d) R 2, R1 and R2 may represent hydrogen and R1 of formula. A process for the preparation of medicaments, characterized in that compounds of general formula (I) according to claim 1 are converted into an appropriate form of administration and, if appropriate, using the usual auxiliaries and excipients. 6ã. Fungus of the Penicillium funiculum strain Thom, characterized in that it has the deposition number DMS 5249. - Process. for preparing compounds of general formula (I) according to claim 1, characterized in that a fungus according to claim 6 is used in said preparation. Lisbon, 11 June 1990 I. PEREIRA DA CRUZ Menta Gficid da Preprledasle Industrial 'iUA VICTOR CCRDSH 10-A, 1. · t200 LISBOA